Epithelial NAIPs protect against colonic tumorigenesis

NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6^Δ/Δ), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6^Δ/Δ mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6^Δ/Δ mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6^Δ/Δ mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6^Δ/Δ mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.Inflammatory bowel disease (IBD) is an important risk factor that favors the development and progression of colitis-associated cancer (CAC; Eaden et al., 2001; Terzić et al., 2010; Rubin et al., 2013). Even in the absence of overt inflammatory disease in colorectal cancer (CRC), loss of barrier function in the tumor epithelium enables translocation of microbial products into tumor tissue. This triggers the activation of lamina propria immunocytes and colonic epithelial cells via pattern-recognition receptors (PRRs) to produce cytokines and chemokines. Those factors then promote tumor growth and mediate recruitment of further immune cells (Grivennikov et al., 2012; Mueller, 2012). Alternatively, epithelial innate immune components could be subverted during tumorigenesis and influence tumor growth independently. Although cytokine/chemokine-mediated modulation of tumor growth has been described, the role of epithelial-intrinsic, innate immune components still remains elusive.Several Nod-like receptors (NLRs) have previously been implicated in colon inflammation and tumorigenesis, mostly in protective roles (Allen et al., 2010; Hu et al., 2010; Chen et al., 2011; Elinav et al., 2011; Zaki et al., 2011; Carvalho et al., 2012). In some cases, this has been attributed to reduced inflammasome-mediated release of IL-18, which is protective for the colonic epithelium (Allen et al., 2010; Dupaul-Chicoine et al., 2010). In other cases, noninflammasome-mediated factors were found to protect mice against CAC development. For example, NLRP12 was protective against colonic inflammation and tumorigenesis by dampening NF-κB and ERK activation in macrophages (Zaki et al., 2011). However, several discrepancies also exist, as illustrated by Caspase-1–deficient mice, which display increased colon tumorigenesis. In one study, this was dependent on NLRC4 and was epithelial intrinsic rather than inflammation mediated (Hu et al., 2010), whereas, in another study, increased tumorigenesis involved NLRP3 and was inflammation and hematopoietic cell–dependent (Allen et al., 2010). Such discrepancies are suggested to arise from differences in microbiota between facilities or use of WT mice from external sources (Ubeda et al., 2012), but could also arise from opposing functions of inflammasome components in different tissues, which has been demonstrated in a skin tumorigenesis model (Drexler et al., 2012).The physiological function of the NLR protein NAIP (NLR family apoptosis inhibitory protein, previously known as neuronal apoptosis inhibitory protein) is not fully characterized, mainly because mice have several possibly redundant Naip paralogs (e.g., 4 functional and 2 noncoding Naip genes in the C57BL/6 genome; Yaraghi et al., 1998; Endrizzi et al., 2000; Growney and Dietrich, 2000). Humans also have several NAIP genes, only one of which is full length (Schmutz et al., 2004; Romanish et al., 2009). NAIPs are intracellular, cytosolic proteins with a tripartite structure; three N-terminal baculovirus inhibitor of apoptosis (IAP) protein repeat (BIR) domains, a central NACHT domain and C-terminal leucine rich-repeat (LRR) domains. The latter two domains group NAIPs to the NLR family of proteins. Indeed, NAIPs are best characterized for their inflammasome function. Mouse and human NAIPs are involved in the detection of intracellular pathogens, such as Salmonella, and activation of the NLRC4 inflammasome, inducing pyroptosis and caspase-1–mediated cleavage of IL-1β and IL-18 (Kofoed and Vance, 2011; Zhao et al., 2011; Rayamajhi et al., 2013; Yang et al., 2013). In mice, NAIP paralogs provide specificity to different bacterial components (Kofoed and Vance, 2011; Zhao et al., 2011). In vivo, the NAIP5-NLRC4 inflammasome was required for sepsis-induced mortality by an Escherichia coli pathobiont or by systemic delivery of intracellular-targeted flagellin, although partial redundancy to other Naip paralogs was apparent (Ayres et al., 2012; von Moltke et al., 2012).NAIPs also belong to the IAP family due to three N-terminal BIR domains; but whether they actually function as inhibitors of apoptosis is controversial. Some studies show direct binding and inhibition of caspase-3 and -9 (Maier et al., 2002; Davoodi et al., 2004, 2010), but others do not (Roy et al., 1997). Also, NAIPs lack certain caspase-interaction residues within the BIR domains that would be necessary for direct inhibition of caspases, raising concern about whether NAIP can inhibit caspases in physiological settings (Scott et al., 2005; Eckelman and Salvesen, 2006; Eckelman et al., 2006). Additionally, NAIPs mediate inflammasome-induced caspase-1 activation and induction of pyroptosis via NLRC4, which is contrary to the suggested inhibitor of apoptosis function (Kofoed and Vance, 2012). BIR domains, however, can mediate a broad range of protein–protein interactions and therefore could be implicated in diverse cellular functions in addition to inhibition of caspases. In NAIPs, the BIR domains appeared to be necessary for NLRC4 inflammasome formation and activation of caspase-1 (Kofoed and Vance, 2011).A mouse model lacking all Naip paralogs has not been available, preventing definitive analysis of NAIPs physiological function. In this study, we describe the first complete Naip1-6 knockout mice and demonstrate a crucial role for NAIPs in preventing colonic tumor initiation and progression.     

Neonatal Severe Hyperparathyroidism due to Compound Heterozygous Mutation of Calcium Sensing Receptor (CaSR) Gene Presenting as Encephalopathy

The authors report a 14-d-old neonate who presented with lethargy, polyuria and dehydration and was found to have severe hypercalcemia with hyperparathyroidism. This neonate was treated with saline hydration, diuresis and injection pamidronate. Genetic analysis revealed a compound heterozygous mutation of CaSR.     

Insoluble drug delivery strategies: review of recent advances and business prospects

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.KEY WORDS: Bioavailability, Cocrystals, Solubility, Inclusion complexation, Nanoparticles, Self-emulsifying formulations, Proliposomes     

Pyriform sinus fistula

Pyriform sinus fistulae/sinuses are rare causes of recurrent cervical abscess, especially on the left side. They can also present as acute thyroiditis. Treatment in the form of simple incision and drainage is invariably unsuccessful, and the entity may be confused with the residual tract of a second branchial arch anomaly. We report a case of pyriform sinus fistula, and believe that this is only the second case report in India. We feel that greater awareness can lead to proper and appropriate diagnosis of this anomaly.     

Synthesis and biological evaluation of a fluorine-18 labeled estrogen receptor-alpha selective ligand: [18F] propyl pyrazole triol

The two estrogen receptor subtypes, ERalpha and ERbeta, play important roles in breast cancer. To develop an ERalpha imaging agent, we synthesized fluoropropyl pyrazole triol (FPPT, 2), an analog of our ERalpha-selective ligand PPT. FPPT retains the high ERalpha binding selectivity of its parent PPT. We prepared [(18)F]FPPT ((18)F-2) in high specific activity, but estrogen target tissue uptake in female rats was minimal and was not displaceable by unlabeled estradiol, probably because of the lipophilicity and triphenolic nature of FPPT.     

Neuropsychiatric non-motor aspects of Parkinson's disease

Parkinson's disease is often recognised as a motor disease characterised by rest tremor, rigidity, bradykinesia, and postural disturbances. However, there are several non-motor aspects of the disease that are of at least equal importance in the management of patients with Parkinson's disease. They include depression, cognitive impairment, anxiety, and psychosis among others. It is important to recognise them, as they are common and they contribute significantly to patients' morbidity, quality of life, and institutionalisation to long term care homes. In addition to the disease duration and severity, other factors including drugs may contribute to their occurrence. Pathogenesis of these aspects is not fully understood, though there has been a significant increase in the knowledge in recent years. Management of these aspects involves a multidisciplinary approach.     

Extraskeletal myxoid chondrosarcoma--a review of three cases

During a ten year period, only three cases of extraskeletal myxoid chondrosarcoma were seen at Kidwai Memorial Institute of Oncology, South India. All were adults; the youngest patient was twenty-six years old and the oldest was seventy five years old. The tumours arose in the soft tissues of the extremities Our findings indicated that tumour size, site and morphology had no bearing on prognosis. With surgery radiotherapy and chemotherapy, two patients survived for four years and nine months respectively and one patient is still on follow up, five months after treatment.