Sarcomatoid cancer of unknown primary site is an aggressive and rare clinical entity associated with poor patient outcomes. We describe a case of a 69-year-old woman who presented with low back pain, right leg weakness, urinary retention, and weight loss. Spinal imaging revealed a soft tissue mass at the right sacral ala infiltrating the S2-S4 neural foramina, with multifocal marrow replacement of the lumbosacral spine and adjacent bilateral iliac bones. Metastatic workup revealed additional lesions of the cervicothoracic spine, left proximal tibia and distal femur, and bilateral pulmonary nodules. Needle biopsy of the sacral mass was consistent with spindle cell carcinoma, a subtype of sarcomatoid carcinoma. IHC staining was positive for GATA3, suggesting mammary or urothelial origin. However, random bladder biopsies obtained at cystoscopy were negative for malignancy and no other discernable primary tumor was identified on full body imaging. This case highlights a rare histologic type of cancer - sarcomatoid carcinoma of unknown primary site (SCUP) in a patient that presented with cauda equina syndrome. Our patient was offered palliative radiation for symptom relief but elected to pursue hospice after the first radiation session. She passed away at a hospice facility within a few months after discharge from the hospital.

Neurosurgery is increasingly performed on patients with significant medical co-morbidities. These could both delay surgery and can lead to postoperative complications. This situation highlights the role played by internal medicine-trained physicians, which include both outpatient providers and hospitalists. In our experience, the best care is provided in close collaboration between neurosurgeons and internal medicine physicians. In this article, we provide the view from the standpoint of a neurosurgeon. Management of co-morbidities by internal-medicine physicians enables neurosurgeons to focus on surgical care, improves patient’s experience and leads to improved resident training.

The theory of immune regulation involves a homeostatic balance between T-helper 1 (Th1) and T-helper 2 (Th2) responses. The Th1 and Th2 theories were introduced in 1986 as a result of studies in mice, whereby T-helper cell subsets were found to direct different immune response pathways. Subsequently, this hypothesis was extended to human immunity, with Th1 cells mediating cellular immunity to fight intracellular pathogens, while Th2 cells mediated humoral immunity to fight extracellular pathogens. Several disease conditions were later found to tilt the balance between Th1 and Th2 immune response pathways, including HIV infection, but the exact mechanism for the shift from Th1 to Th2 cells was poorly understood. This review provides new insights into the molecular biology of HIV, wherein the HIV life cycle is discussed in detail. Insights into the possible mechanism for the Th1 to Th2 shift during HIV infection and the preferential infection of Th2 cells during the late symptomatic stage of HIV disease are also discussed.

Management of patients that undergo neurosurgery increasingly involves hospitalists. In this article, we outline and discuss the roles of these neurosurgery hospitalists, and training which is required. We describe both commonalities of their work with hospitalists which take care of non-neurosurgical patients, as well as the differences. We highlight the decision process which led to forming of the first of its kind fellowship, which builds on the new body of knowledge which accumulated over years. We believe that extended training of neurosurgery hospitalists will lead to increased quality of patient care.

Supplementary Video 2 from Abnormal Cytokinesis after X-Irradiation in Tumor Cells that Override the G2 DNA Damage Checkpoint

Drug abuse is a common comorbidity in people infected with HIV. HIV-infected individuals who abuse drugs are a key population who frequently experience suboptimal outcomes along the HIV continuum of care. A modest proportion of HIV-infected individuals develop HIV-associated neurocognitive issues, the severity of which further increases with drug abuse. Moreover, the tendency of the virus to go into latency in certain cellular reservoirs again complicates the elimination of HIV and HIV-associated illnesses. Antiretroviral therapy (ART) successfully decreased the overall viral load in infected people, yet it does not effectively eliminate the virus from all latent reservoirs. Although ART increased the life expectancy of infected individuals, it showed inconsistent improvement in CNS functioning, thus decreasing the quality of life. Research efforts have been dedicated to identifying common mechanisms through which HIV and drug abuse lead to neurotoxicity and CNS dysfunction. Therefore, in order to develop an effective treatment regimen to treat neurocognitive and related symptoms in HIV-infected patients, it is crucial to understand the involved mechanisms of neurotoxicity. Eventually, those mechanisms could lead the way to design and develop novel therapeutic strategies addressing both CNS HIV reservoir and illicit drug use by HIV patients.

Neurosurgery hospitalists will continue to be closely involved in the management of patients which undergo neurosurgery. In the first article, we discuss the tremendous potential of the service for improving the care for neurosurgical patients at Jefferson. We highlight the interactions with other services and the areas for potential growth. Further, we emphasize the need for constant feedback, which is necessary to improve the care provided by FHS.

Neurosurgery hospitalists are closely involved in management of patients that undergo neurosurgery. In this article, we outline and discuss the major aspects of the work of these physicians. We emphasize the crucial role of these physicians in both preoperative and postoperative care as well as their roles in education and research. We also highlight the work of the Farber Hospitalist Service (FHS) for the last 5 year period, and point out the differences between FHS and other neurosurgery hospitalist services nationwide. It is hoped that this article will shed light on the work of neurosurgery hospitalists and help to clarify their roles in patient care.

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting polycomb group (PcG/PRC) corepressor complexes or polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, the treatment of latently infected primary CD4+ T cells with the PRC2/EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Extracellular vesicles (EVs) play an important role in intercellular communication. They are naturally released from cells into the extracellular environment. Based on their biogenesis, release pathways, size, content, and function, EVs are classified into exosomes, microvesicles (MVs), and apoptotic bodies (ApoBDs). Previous research has documented that EVs, specifically exosomes and MVs, play an important role in HIV infection, either by promoting HIV infection and pathogenesis or by inhibiting HIV-1 to a certain extent. We have also previously reported that EVs (particularly exosomes) from vaginal fluids inhibit HIV at the post-entry step (i.e., reverse transcription, integration). Besides the role that EVs play in HIV, they are also known to regulate the process of wound healing by regulating both the immune and inflammatory responses. It is noted that during the advanced stages of HIV infection, patients are at greater risk of wound-healing and wound-related complications. Despite ongoing research, the data on the actual effects of EVs in HIV infection and wound healing are still premature. This review aimed to update the current knowledge about the roles of EVs in regulating HIV pathogenesis and wound healing. Additionally, we highlighted several avenues of EV involvement in the process of wound healing, including coagulation, inflammation, proliferation, and extracellular matrix remodeling. Understanding the role of EVs in HIV infection and wound healing could significantly contribute to the development of new and potent antiviral therapeutic strategies and approaches to resolve impaired wounds in HIV patients.

Hyperglycemia is associated with adverse outcomes in patients who are candidates for or underwent neurosurgical procedures. Specific concerns and settings that relate to these patients are preoperative glycemic control, intraoperative control, management in the neurological intensive care unit (NICU), and postoperative control. In each of these settings, physicians have to ensure appropriate glycemic control to prevent or minimize adverse events. The glycemic control is usually managed by a neurohospitalist in co-management with the neurosurgery team pre- and postoperatively, and by the neurocritical care team in the setting of NICU. In this review article, we outline current standards of care for neurosurgery patients with diabetes mellitus and/or and hyperglycemia and discuss results of most recent clinical trials. We highlight specific concerns with regards to glycemic controls in these patients including enteral tube feeding and parenteral nutrition, the issues of the transition to the outpatient care, and management of steroid-induced hyperglycemia. We also note lack of evidence in some important areas, and the need for more research addressing these gaps. Where possible, we provide suggestions how to manage these patients when there is no underlying guideline.

Vibrio is a genus of Gram-negative motile rods. Several species are pathogenic, including Vibrio vulnificus and Vibrio parahaemolyticus. The interest in this genus is due to its extreme virulence and often fatal outcomes. In healthy patients, these infections are typically self-limited; however, in immunocompromised and cirrhotic patients, infections can result in bacteremia, which has a high fatality rate1. Both pathogens may cause acute gastroenteritis, necrotizing wound infections, and if severe, subsequent bacteremia. In this report, we present two cases of Vibrio infections recently identified in the Delaware River Estuary that resulted in severe sepsis and, in one case, death.

Objective:Vaginal transmission is crucial to the spread of HIV-1 around the world. It is not yet clear what type (s) of innate defenses against HIV-1 infection are present in the vagina. Here, we aimed to determine whether human vaginal fluid contains exosomes that may possess anti-HIV-1 activity. Methods:The exosomal fraction was isolated from samples of vaginal fluids. The presence of exosomes was confirmed by flow cytometry and western blotting. The newly discovered exosomes were tested for their ability to block early steps of HIV-1 infection in vitro using established cell culture systems and real time PCR-based methods. Results:Vaginal fluid contains exosomes expressing CD9, CD63, and CD81 exosomal markers. The exosomal fraction of the fluid-reduced transmission of HIV-1 vectors by 60%, the efficiency of reverse transcription step by 58.4%, and the efficiency of integration by 47%. Exosomes had no effect on the entry of HIV-1 vectors. Conclusion:Human vaginal fluid exosomes are newly discovered female innate defenses that may protect women against HIV-1 infection.

Replication-deficient retroviruses have been successfully utilized as vectors, offering an efficient, stable method of therapeutic gene delivery. Many examples exist proving this mode of integrative gene transfer is both effective and safe in cultured systems and clinical trials. Along with their success, severe side effects have occurred with early retroviral vectors causing a shift in the approach to vector design before further clinical testing. Several alternative delivery methods are available but lentiviral vectors (LV) are among the most favorable as they are already well understood. LV offer safer integration site selection profiles and a lower degree of genotoxicity, compared with γ-retroviral vectors. Following their introduction, development of the self-inactivating vector configuration was a huge step to this mode of therapy but did not confer full protection against insertional mutagenesis. As a result integration, modeling must be improved to eventually avoid this possibility. The cellular factor LEDGF/p75 seems to play an essential role in the process of LV site selection and its interactions with chromatin are being quickly resolved. LEDGF/p75 is at the center of one example directed integration effort where recombinant products bias the integration event, a step toward fully directed integration into pre-determined benign loci. A more accurate picture of the details of LEDGF/p75 in the natural integration process is emerging, including new binding specificities, chromatin interaction kinetics and additional cellular factors. Together with next-generation sequencing technology and bio-informatics to analyze integration patterns, these advancements will lead to highly focused directed integration, accelerating wide-spread acceptance of LV for gene therapy.

Aging is a process that involves all organs and tissues of the human organism. Cells and tissues are impacted by aging in differing degrees, depending on their regenerative potential and sensitivity to outside stimuli. In this review, we discuss the potential role of adult stem cells in the aging process, and the new results that support the role of stem cells in the aging process. Finally, we discuss new evidence from progeroid syndromes that supports the stem cell hypothesis of aging.

This chapter contains sections titled: Introduction Post Integration Repair Establishment of Epigenetic Properties Conclusions References

HIV-1-based vectors are widely used in gene therapy. In somatic cells, these vectors mainly integrate within genes. However, no distinct integration site preferences have been observed with regard to large chromosomal regions. The recent emergence of induced pluripotent stem (iPS) cells, similar to embryonic stem (ES) cells, has raised questions about where integration occurs in these cells. In this work we investigated the integration site preferences of HIV-1-based vectors in a pluripotent, ES-like cell line. We show that approximately 30% of the integrations occur in the vicinity of telomeres. We have analyzed integration sites in various somatic cells, as reported by us and other groups, and observed that this integration pattern is unique to the analyzed pluripotent cell line. We conclude that pluripotent cells may contain distinct cellular cofactors that participate in integration targeting and that are not present in somatic cells.

Retroviral vectors have gained an increasing value in gene therapy because they stably deliver therapeutic genes to the host cell genome. These therapeutic genes are supposed to rectify consequences of inherited and acquired mutated genes in the host cell genome, or alter host cell function to cure diseases. In the following section we will discuss the biology and life cycle of retroviruses which starts with viral entry into the host cell, reverse transcription of viral RNA, nuclear import of the provirus, and finally integration of viral DNA into the cell host genome (Flint, Racaniello et al. 2004). Integration involves viral and host cellular proteins. Their role is discussed in the third and fourth sections of this chapter. Recently, the process of integration site selection (which is where the viral DNA integrates with the host cell DNA) has been quite understood throughout many in vitro and in vivo studies. The human genome project has enabled us to identify integration site preferences for retroviral vectors in human trials. The results of these human trials are reviewed in the fifth section of the chapter. Finally, the last section of the chapter will demonstrate the latest gene therapy trials attempts to control integration sites by manipulation of retrovirus genes and proteins.

Efficient HIV-1 transduction depends on a number of cellular co-factors. Cellular double-strand DNA break (DSB) repair proteins have been proposed, by ourselves and others, to be required for efficient HIV-1 transduction. Expression and/or activity of these DNA repair proteins can be induced by the introduction of DSBs into the host cell genome. HIV-1 transduction was up-regulated by treatment with DSB-inducing agents in both drug-arrested cells and differentiated neuronal cells. The presented data support the hypothesis that DSB repair proteins are involved in the early steps of the retroviral life-cycle.