The foundational framework of tumors: Gametogenesis, p53, and cancer.

The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.

A Paradigm Shift in Critical Care Infrastructure in Complex Settings: Evaluating an Ultraportable Operating Room to Improve Field Surgical Safety.

INTRODUCTION: Scarcity of operating rooms and personal protective equipment in far-forward field settings make surgical infections a potential concern for combat mortality and morbidity. Surgical and transport personnel also face infectious risks from bodily fluid exposures. Our study aimed to describe the serial, proof-of-concept testing of the SurgiBox technology: an inflatable sterile environment that addresses the aforementioned problems, fits on gurneys and backpacks, and drapes over incisions. MATERIALS AND METHODS: The SurgiBox environmental control unit and inflatable enclosure were optimized over five generations based on iterative feedback from stakeholders experienced in surgery in austere settings. The airflow system was developed by analytic modeling, verified through in silico modeling in SOLIDWORKS, and confirmed with prototype smoke-trail checking. Particulate counts evaluated the enclosure's ability to control and mitigate users' exposures to potentially infectious contaminants from the surgical field in various settings. SurgiBox enclosures were setup over a mannequin's torso, in a configuration and position for either thoracic or abdominal surgery. A particle counter was serially positioned in sternotomy and laparotomy positions, as well as bilateral flank positions. This setup was repeated with open ports exposing the enclosure to the external environment. To simulate stress scenarios, sampling was repeated with enclosure measurements during an increase in external particulate concentration. RESULTS: The airflow technology effectively kept contaminants away from the incision and maintained a pressure differential to reduce particle entry. Benchtop testing demonstrated that even when ports were opened or the external environment had high contaminant burden, the enclosed surgical field consistently registered 0 particle count in all positions. Time from kit opening to incision averaged 54.5 seconds, with the rate-limiting step being connecting the environmental control unit to the enclosure. The portable kit weighted 5.9 lbs. CONCLUSIONS: Analytic, in silico, and mechanical airflow modeling and benchtop testing have helped to quantify the SurgiBox system's reliability in creating and maintaining an operating room-quality surgical field within the enclosure as well as protecting the surgical team outside the enclosure. More recent and ongoing work has focused on specifying optimal use settings in the casualty chain of care, expanding support for circumferential procedures, automating airflow control, and accelerating system setup. SurgiBox's ultimate goal is to take timely, safe surgery to patients in even the most austere of settings.

The Skp2 Pathway: A Critical Target for Cancer Therapy.

Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.

Global Health Engagement and The Department of Defense as a Vehicle for Security and Sustainable Global Health.

The Unites States Department of Defense (DoD) is viewed by many in the general public as a monolithic government entity whose primary purpose is to coordinate this country's ability to make war and maintain a military presence around the world. However, the DoD is in fact a multidimensional organization whose global impact is as expansive as it is varying and is responsible for far-reaching global health interventions. The United States has worked toward providing long-term care among host nation populations by providing training in several areas related to medicine, with positive results. These efforts can be built upon with substantial positive effects. Building health infrastructure and capacity around the world is essential. The DoD is the most generously funded agency in the world, and the resources at its disposal provide the opportunity to make great gains in the long term in terms of both health and security worldwide. With efficient and careful use of DoD resources, and partnerships with key non-governmental organizations with specialized knowledge and great passion, partnerships can be forged with communities around the world to ensure that public health is achieved in even the most underserved communities. A move toward creating sustainable health systems with long-term goals and measurable outcomes is an essential complement to the already successful disaster and emergency relief that the United States military already provides. By ensuring that communities around the world are both provided with access to the sustainable health care they need and that emergency situations can be responded to in an efficient way, the United States can serve its duty as a leader in sharing expertise and resources for the betterment and security of all humankind.

Akt: a new activation mechanism.

Akt phosphorylation at S473 and T308 has been believed to be the prerequisites for its activation for years. Now, new phosphorylation event on Akt is identified and can trigger Akt activation and lead to its downstream oncogenic events.

The nano-plasma interface: Implications of the protein corona.

The interactions between nanoparticles and macromolecules in the blood plasma dictate the biocompatibility and efficacy of nanotherapeutics. Accordingly, the properties of nanoparticles and endogenous biomolecules change at the nano-plasma interface. Here, we review the implications of such changes including toxicity, immunological recognition, molecular targeting, biodistribution, intracellular uptake, and drug release. Although this interface poses several challenges for nanomedicine, it also presents opportunities for exploiting nanoparticle-protein interactions.

Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression.

Skp2 E3 ligase is overexpressed in numerous human cancers and plays a critical role in cell-cycle progression, senescence, metabolism, cancer progression, and metastasis. In the present study, we identified a specific Skp2 inhibitor using high-throughput in silico screening of large and diverse chemical libraries. This Skp2 inhibitor selectively suppresses Skp2 E3 ligase activity, but not activity of other SCF complexes. It also phenocopies the effects observed upon genetic Skp2 deficiency, such as suppressing survival and Akt-mediated glycolysis and triggering p53-independent cellular senescence. Strikingly, we discovered a critical function of Skp2 in positively regulating cancer stem cell populations and self-renewal ability through genetic and pharmacological approaches. Notably, Skp2 inhibitor exhibits potent antitumor activities in multiple animal models and cooperates with chemotherapeutic agents to reduce cancer cell survival. Our study thus provides pharmacological evidence that Skp2 is a promising target for restricting cancer stem cell and cancer progression.

Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling.

K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor-mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor-induced ubiquitination of Akt have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquitination of Akt and the function of Akt deubiquitination remain largely unclear. We showed that CYLD was a DUB for Akt and suppressed growth factor-mediated ubiquitination and activation of Akt. CYLD directly removed ubiquitin moieties from Akt under serum-starved conditions. CYLD dissociated from Akt upon growth factor stimulation, thereby allowing E3 ligases to induce ubiquitination and activation of Akt. CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake, and, when injected into mice, growth of prostate tumors. Our findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in determining its plasma membrane localization and activation--and further identify CYLD as a molecular switch for these processes.

The role of Skp2 in hematopoietic stem cell quiescence, pool size, and self-renewal.

Although the maintenance of HSC quiescence and self-renewal are critical for controlling stem cell pool and transplantation efficiency, the mechanisms by which they are regulated remain largely unknown. Understanding the factors controlling these processes may have important therapeutic potential for BM failure and cancers. Here, we show that Skp2, a component of the Skp2 SCF complex, is an important regulator for HSC quiescence, frequency, and self-renewal capability. Skp2 deficiency displays a marked enhancement of HSC populations through promoting cell cycle entry independently of its role on apoptosis. Surprisingly, Skp2 deficiency in HSCs reduces quiescence and displays increased HSC cycling and proliferation. Importantly, loss of Skp2 not only increases HSC populations and long-term reconstitution ability but also rescues the defect in long-term reconstitution ability of HSCs on PTEN inactivation. Mechanistically, we show that Skp2 deficiency induces Cyclin D1 gene expression, which contributes to an increase in HSC cycling. Finally, we demonstrate that Skp2 deficiency enhances sensitivity of Lin(-) Sca-1(+) c-kit(+) cells and leukemia cells to chemotherapy agents. Our findings show that Skp2 is a novel regulator for HSC quiescence and self-renewal and that targeting Skp2 may have therapeutic implications for BM transplantation and leukemia stem cell treatment.

Novel ARF/p53-independent senescence pathways in cancer repression.

Cellular senescence, which can be induced by various stimuli, is a stress response that manifests as irreversible cell cycle arrest. Recent studies have revealed that cellular senescence can serve as a critical barrier for cancer development. Induction of cellular senescence by oncogenic insults, such as Ras overexpression or by inactivation of PTEN tumor suppressor, triggers an ARF/p53-dependent tumor-suppressive effect which can significantly restrict cancer progression. Given the important role of the ARF/p53 pathway in cellular senescence and tumor suppression, drugs that stabilize p53 expression have been developed and tested in clinical trials. However, a major hurdle for p53 targeting in cancer treatment arises from the frequent deficiency or mutation of ARF or p53 in human cancers, which, in turn, profoundly compromises their tumor-suppressive ability. Recent discoveries of novel regulators involved in ARF/p53-independent cellular senescence not only reveal novel paradigms for cellular senescence but also provide alternative approaches for cancer therapy.