Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. Here we demonstrate that depletion of the autophagic proteins LC3B and beclin 1 enhanced the activation of caspase-1 and secretion of interleukin 1β (IL-1β) and IL-18. Depletion of autophagic proteins promoted the accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial reactive oxygen species (ROS). Cytosolic mtDNA contributed to the secretion of IL-1β and IL-18 in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity.

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Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

Cancer immunotherapy via dendritic cells

Background: In patients with large dural defects of the anterior and ventral skull base after endonasal skull base surgery, there is a significant risk of a postoperative cerebrospinal fluid leak after reconstruction. Reconstruction with vascularized tissue is desirable to facilitate rapid healing, especially in irradiated patients.

Methods: We developed a neurovascular pedicled flap of the nasal septum mucoperiosteum and mucoperichondrium based on the nasoseptal artery, a branch of the posterior septal artery (Hadad-Bassagasteguy flap [HBF]). A retrospective review of patients undergoing endonasal skull base surgery at the University of Rosario, Argentina, and the University of Pittsburgh Medical Center was performed to identify patients who were reconstructed with a vascularized septal mucosal flap.

Results: Forty-three patients undergoing endonasal cranial base surgery were repaired with the septal mucosal flap. Two patients with postoperative cerebrospinal fluid leaks (5%) were successfully treated with focal fat grafts. We encountered no infectious or wound complications in this series of patients. One patient experienced a posterior nose bleed from the posterior nasal artery. This was controlled with electrocautery and the flap blood supply was preserved.

Conclusion: The HBF is a versatile and reliable reconstructive technique for defects of the anterior, middle, clival, and parasellar skull base. Its use has resulted in a sharp decrease in the incidence of postoperative cerebrospinal fluid leaks after endonasal skull base surgery and is recommended for the reconstruction of large dural defects and when postoperative radiation therapy is anticipated.

A novel reconstructive technique after endoscopic expanded endonasal approaches : Vascular pedicle nasoseptal flap

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.

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Coronaviruses - drug discovery and therapeutic options.

Oxidative stress and cancer: an overview.

Object. Transsphenoidal approaches have been used for a century for the resection of pituitary and other sellar tumors. More recently, the standard endonasal approach has been expanded to provide access to other, parasellar lesions. With the addition of the endoscope, this expansion carries significant potential for the resection of skull base lesions. Methods. The anatomical landmarks and surgical techniques used in expanded (extended) endoscopic approaches to the rostral, anterior skull base are reviewed and presented, accompanied by case illustrations of each segment (or module) of approach. The rostral half of the anterior skull base is divided into modules of approach: sellar/parasellar, transplanum/transtuberculum, and transcribriform. Case illustrations of successful resections of lesions with each module are presented and discussed. Conclusions. Endoscopic, expanded endonasal approaches to rostral anterior skull base lesions are feasible and hold great potential for decreased morbidity. The effectiveness and appropriate use of these techniques must be evaluated by close examination of outcomes as case series expand.

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Expanded endonasal approach: the rostrocaudal axis. Part I. Crista galli to the sella turcica

Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha.

Objective Reconstruction of the cranial base using vascularized tissue promotes rapid and complete healing, thus avoiding complications caused by persistent communication between the cranial cavity and the sinonasal tract. The Hadad-Bassagasteguy flap (HBF), a neurovascular pedicled flap of the nasal septum mucoperiosteum and mucoperichondrium based on the nasoseptal artery, seems to be advantageous for the reconstruction of the cranial base after endonasal cranial base surgery. Methods We performed a retrospective review of patients who underwent endonasal cranial base surgery at the University of Pittsburgh Medical Center from January 30, 2006 to January 30, 2007, identifying patients who experienced reconstruction with a vascularized septal mucosal flap (HBF). We analyzed the demographic data, pathological characteristics, site and extent of resection, use of cerebrospinal fluid (CSF) diversion techniques, and outcome. Results Seventy-five patients who underwent endonasal cranial base endoscopic surgery received repair with the HBF. In this population, we encountered eight postoperative CSF leaks (10.66%), all in patients who required intra-arachnoidal dissection. When we correct the statistical analysis to include only patients with intra- arachnoidal lesions, the postoperative CSF leak rate is 14.5% (eight of 55 patients). It is notable that six CSF (33%) leaks occurred in our first 25 repairs, whereas we encountered only two postoperative leaks (4%) in the last 50 patients. The corrected CSF leak rate, considering only intra-arachnoidal lesions, was two (5.4%) of 37 patients. This improvement in the CSF leak rate reflects our growing experience and comfort with this reconstructive technique. All of our failures could be matched to a specific technical mistake. In addition, we modified the flap-harvesting technique to allow for staged procedures and the removal of caudal lesions. These special circumstances require storage of the flap in the antrum during the removal of caudal lesions, and suturing of the flap in its original position for staged procedures. One patient experienced a posterior nose bleed from the posterior nasal artery. This was controlled with bipolar electrocautery, thereby preserving the flap blood supply. We encountered no infectious or wound complications in this series of patients. The donor site accumulates crusting, which requires debridement until mucosalization is complete; this usually occurs 6 to 12 weeks after surgery. Conclusion The HBF is a versatile and reliable reconstructive technique for repairing defects of the anterior, middle, clival, and parasellar cranial base. Its use has resulted in a significant decrease in our incidence of CSF leaks after endonasal cranial base surgery. Attention to technical details is of paramount importance to achieve the best outcomes.

Endoscopic reconstruction of the cranial base using a pedicled nasoseptal flap.

Object The middle third of the clivus and the region around the petrous internal carotid artery (ICA) is a difficult area of the skull base in terms of access. This is a deep area rich with critical neurovascular structures, which is often host to typical skull base diseases. Expanded endoscopic endonasal approaches offer a potential option for accessing this difficult region. The objective of this paper was to establish the clinical feasibility of gaining access to the paraclival space in the region of the middle third of the clivus, to provide a practical modular and clinically applicable classification, and to describe the relevant critical surgical anatomy for each module. Methods The anatomical organization of the region around the petrous ICA, cavernous sinus, and middle clivus is presented, with approaches divided into zones. In an accompanying paper in this issue by Cavallo, et al., the anatomy of the pterygopalatine fossa is presented; this was observed through cadaveric dissection for which an e...

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Expanded endonasal approach: fully endoscopic, completely transnasal approach to the middle third of the clivus, petrous bone, middle cranial fossa, and infratemporal fossa.

Arlan Mintz

Papers

A novel reconstructive technique after endoscopic expanded endonasal approaches : Vascular pedicle nasoseptal flap

Expanded endonasal approach: the rostrocaudal axis. Part I. Crista galli to the sella turcica

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha.

Endoscopic reconstruction of the cranial base using a pedicled nasoseptal flap.

Expanded endonasal approach: fully endoscopic, completely transnasal approach to the middle third of the clivus, petrous bone, middle cranial fossa, and infratemporal fossa.