Annexin 1 (ANXA1) is an endogenous anti-inflammatory protein implicated in cancer. ANXA1 was previously shown to be regulated by hsa-miR-196a. However, whether ANXA1 itself regulates microRNA (miR) expression is unknown. Therefore, we investigated the regulation of miR by ANXA1 in MCF7 breast cancer cells. MCF7-EV (Empty vector) and MCF7-V5 (ANXA1-V5 expressing cells) were subjected to a miR microarray. Microarray analysis revealed a number of miRNAs which were dysregulated in MCF7-V5 cells. 2 novel miRNAs (miR562 and miR26b*) were validated, cloned and functionally characterized. As ANXA1 constitutively activates NF-κB activity to modulate breast cancer metastasis, we found that miR26b* and miR562 directly targeted the canonical NF-κB pathway by targeting the 3′ UTR and inhibiting expression of Rel A (p65) and NF-κB1 (p105) respectively. MiR562 inhibited wound healing, which was reversed when ANXA1 was overexpressed. Overexpression of either miR562 or miR26b* in MCF-7 cells enhanced endothelial tube formation when cocultured with human umbilical cord endothelial cells while conversely, treatment of MCF7 cells with either anti-miR562 or anti-miR26b* inhibited endothelial tube formation after co-culture. Further analysis of miR562 revealed that miR562-transfected cell conditioned media enhances endothelial cell tube formation, indicating that miR562 increased angiogenic secreted factors from MCF-7 breast tumor cells. TNFα was increased upon overexpression of miR562, which was reversed when ANXA1 was co-transfected In conclusion, this data suggests that ANXA1-regulated miR26b* and miR562 may play a role in wound healing and tumor-induced endothelial cell tube formation by targeting NF-κB expression and point towards a potential therapeutic target for breast cancer.
Chronic rhinosinusitis (CRS) is a major cause of concern worldwide. Nasal septal deviation (NSD) may either cause osteomeatal obstruction or may interfere with proper airflow and potentially predispose to sinusitis. Due to the lack of a universally accepted classification on NSD it has not been established whether NSD influences the development of sinusitis or not. Mladina in 1987 proposed a classification in which he classified NSD into seven different categories. The aims and objectives of this study are to observe the correlation between NSD and CRS and to study the relation of different grades of NSD with sinusitis as per Mladina's classification. Patients above 18 years of age presenting to ENT OPD with complaint of nasal obstruction, nasal discharge and headache were subjected to CT scan (nose and paranasal sinuses) coronal section with contiguous 5 mm thickness slice perpendicular to the hard palate in prone position. Presence of NSD and sinusitis was observed. 120 cases were studied. The mean age was 28.7 ± 9.37 years with age range 18–58 years. There were 92 (76.6 %) males and 28 (23.3 %) females with a M:F ratio of 3:1. Out of 120 cases, 114 (95 %) cases had NSD. Sinusitis was present in 63 (52.5 %) cases on CT scan. Out of 57 (50.0 %) cases with NSD and sinusitis, 13 (11.4 %) cases had sinusitis on the same side of NSD, 14 (12.28 %) cases had sinusitis on the side opposite to NSD and 30 (26.31 %) cases had sinusitis on both sides of NSD. There was no statistically significant relationship between NSD and sinusitis. As per Mladina's classification vertical deviations accounted for majority of patient’s septal deviations with 31 (27.1 %) cases of type II NSD and 24 (21.1 %) cases of type I NSD. The maximum number of cases with sinusitis had vertical deviations with type I NSD in 17 (27.0 %) cases and type II NSD in 18 (28.5 %) cases. The present study reveals that there is no correlation between NSD and sinusitis. Vertical deviations type I and type II are more prone to sinusitis as they involve the nasal valve area.
Deviated septum; Rhinosinusitis
Acinetobacter baumannii is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling A. baumannii are not well understood. Although viewed as an extracellular pathogen, A. baumannii can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against A. baumannii is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of A. baumannii by human airway epithelial cells in vitro. A. baumannii infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of A. baumannii in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of A. baumannii infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for A. baumannii infection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to A. baumannii infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of A. baumannii infection through the production of β-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of A. baumannii and may contribute to the development of effective immune therapeutics and vaccines against A. baumannii.
Advances in optics, miniaturization, and endoscopic instrumentation have revolutionized surgery in the past decade. Current progress in the field of endoscopy promises to further this evolution: endoscopic telescopes and instruments have improved upon the optical and technical limitations of the microscope, and require an even less invasive approach to the sella. Pituitary surgery is traditionally within the realm of the neurosurgeon. However, since the reintroduction of the transseptal transsphenoidal approach and endoscopic transnasal transsphenoidal approach to the sella turcica for resection of pituitary adenoma, otolaryngologists have been active partners in the surgical management of these patients. Otolaryngologists have lent their expertise in nasal and sinus surgery, assisting the neurosurgeon with the operation. The otolaryngologist has the advantage of familiarity with the techniques and instruments used to gain exposure of the sella turcica by transnasal approach. Hence, the otolaryngologist provides the exposure, and the neurosurgeon resects the tumour. Such collaboration has resulted in decreased rates of complication and morbidity. We hereby discuss our experience of treating 54 cases of pituitary tumour by endoscopic transnasal approach at our hospital.
Pituitary surgery transsphenoidal; Pituitary adenoma; Transphenoid surgery; Endoscopic hypophysectomy
Pharynx is a common site of malignancy in the head and neck region. This study presents a series of 94 cases of pharyngeal malignancy conducted at Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand in the Department of Otorhinolaryngology for a period of one year (2009–2010). Mean age at presentation was 56.8 years (age range 18–100 years). Male:Female ratio was 8.4:1.0. Maximum patients belonged to lower socio-economic status as per Kuppuswamy’s classification (2003). Majority of them were farmer (38.2%) by occupation and belonged to rural areas. 90.4% patients had history of tobacco smoking. Dysphagia was the commonest chief complaint. The most common subsite was oropharynx (51.0%) followed by hypopharynx (45.7%). Ulceroproliferative growth was the most common clinical finding. Histopathologically, squamous cell carcinoma (94.6%) was the commonest. CECT was the commonest and most useful radiological investigation done to see the extent of the disease.
Oropharynx malignancy; Pharynx malignancy; Nasopharynx; Hypopharynx malignancy
A high throughput electrochemiluminescent (ECL) chip was fabricated and integrated into a fluidic system for screening toxicity-related chemistry of drug and pollutant metabolites. The chip base is conductive pyrolytic graphite onto which are printed 64 microwells capable of holding one-µL droplets. Films combining DNA, metabolic enzymes and an ECL-generating ruthenium metallopolymer (RuIIPVP) are fabricated in these microwells. The system runs metabolic enzyme reactions, and subsequently detects DNA damage caused by reactive metabolites. The performance of the chip was tested by measuring DNA damage caused by metabolites of the well-known procarcinogen benzo[a]pyrene (B[a]P). Liver microsomes and cytochrome P450 (cyt P450) enzymes were used with and without epoxide hydrolase (EH), a conjugative enzyme required for multi-enzyme bioactivation of B[a]P. DNA adduct formation was confirmed by determining specific DNA-metabolite adducts using similar films of DNA/enzyme on magnetic bead biocolloid reactors, hydrolyzing the DNA, and analyzing by capillary liquid chromatography-mass spectrometry (CapLC-MS/MS). The fluidic chip was also used to measure IC50-values of inhibitors of cyt P450s. All results show good correlation with reported enzyme activity and inhibition assays.
Nose bleed is the most common rhinological emergency. There are multiple risk factors for the development of epistaxis and it can affect any age group, but it is the elderly population with their associated morbidity who often require more intensive treatment and subsequent admission. Most cases of epistaxis occur in the Little’s area, a location readily accessible and treatable by cautery or anterior nasal packing. However, posterior epistaxis often requires more aggressive measures including posterior nasal packing and endoscopic cauterization. After posterior nasal packing, the two most common therapies for intractable epistaxis are transantral ligation of the internal maxillary artery and percutaneous embolization of the distal internal maxillary artery. However, optimal management of intractable posterior epistaxis remains controversial. We hereby report fourth case of Waldenstrom Macroglobulinemia in English literature, which presented as isolated persistent epistaxis and was treated by therapeutic plasmapheresis.
Epistaxis; Little’s area; Embolization; Plasmapheresis; Waldenstrom macroglobulinemia
The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications.
The innate immune system is critical for viral infection control by host organisms. The type I interferons are a family of major antiviral cytokines produced upon the activation of innate immune pattern recognition receptors (PRRs) by viruses. The RIG-I is a major PRR that uniquely detects RNA viruses within the cytoplasm. In this study, we aimed to discover cellular genes and pathways that play regulatory roles in the transcriptional induction of type I interferon-β (IFNβ). Using a human genome wide RNA interference (RNAi) screening, we identified 226 genes whose expression is important for proper IFNβ production. Through bioinformatics-based mining of the RNAi screen results, we identified that the cellular pathway synthesizing inositol pyrophosphates, a class of inositol phosphates with high-energy diphosphates, is a key positive regulator of RIG-I mediated IFNβ production. The kinases IPPK, PPIP5K1 and PPIP5K2, that synthesize inositol pyrophosphate 1-IP7, regulated IFNβ response in a catalytically dependent manner. Mechanistic studies identified that 1-IP7 synthesis pathway was needed for efficient phosphorylation of IRF3. The DIPP family of inositol pyrophosphate hydrolases negatively regulated the IFNβ response, upon ectopic expression. In summary, this study generated a global view of the regulation of RIG-I signaling, and identified inositol pyrophosphates as important regulators of antiviral response.
Scrub typhus is a major infectious threat in the Asia-Pacific region. We report an unusual case of scrub typhus in a patient in Singapore who presented with sepsis and acute respiratory distress syndrome but lacked the pathognomonic eschar. The patient recovered after appropriate diagnosis and doxycycline treatment. Rickettsial diseases should be included in the differential diagnosis of febrile illnesses in regions where the diseases are endemic, and absence of eschar should not be the criterion used to rule out scrub typhus.
Fungus cerebri is a relatively rare disease. The various reasons attributed to such pathology are, long standing mastoiditis, previous temporal lobe fracture, spontaneous herniation and most important common cause is post operative to mastoidectomy. The diagnosis is mainly clinical and supplemented by imaging studies. The commonly herniated part is the temporal lobe, but cerebellar herniation are also reported Different surgical modalities are used in managing this condition. Surgical approaches in the treatment of brain herniation into the mastoid or middle ear are, neurosurgical, otosurgical and combined. A case of fungus cerebri complicating mastoidectomy is presented and the pathogenesis is discussed
Brain fungus; Fungus cerebri; Masoidectomy
The purpose of this study was to identify patients of vocal cord paralysis and to establish an etiological diagnosis. Patients with vocal cord paralysis have been followed prospectively at a tertiary referral center. 120 patients identified with vocal cord paralysis by laryngeal endoscopy were evaluated clinically, radiologically and pathologically to make an etiological diagnosis. Those patients in whom no cause was found, a CT scan from base of skull to thorax was done before labeling them as idiopathic. Most of the patients presented in 5th (26.67 %) and 6th (21.67 %) decade. Males out numbered females in the ratio 2.3:1.0. The most common symptom of vocal cord paralysis was change in voice (98.21 %). Bilateral vocal cord palsy was found in 6.67 % patients and unilateral vocal cord palsy was found in 93.33 % patients. Among patients of unilateral vocal cord paralysis left vocal cord was paralyzed in 69.64 % and right cord in 30.36 %. Malignant (34.16 %) causes accounted for largest number of patients followed by central (15.00 %) and idiopathic causes (14.16 %). VCP has got a variable etiology which varies with the laterality of the vocal cord involvement. Malignant causes predominated in our series, occurring in 34.16 %, followed by central and idiopathic causes.
Vocal cord paralysis (VCP); Unilateral vocal cord paralysis (UVCP); Bilateral vocal cord paralysis (BVCP); Etiology
Self-inflicted eye injuries among psychiatric patients are rare but important group of ophthalmic conditions that require close cooperation between different medical specialties to ensure optimum care of the severely disturbed patient. They have been associated with a variety of disorders, including paranoid schizophrenia, drug-induced psychosis, obsessive-compulsive disorder, depression, mental retardation, and ritualistic behavior. It has been described in both adults and children, but occurs most commonly in young adults with acute or chronic psychoses.
Self-inflicted; ocular injury; needle
Accumulating evidence(s) indicate that CXCL12-CXCR4 signaling cascade plays an important role in the process of invasion and metastasis that accounts for more than 80% of deaths in hepatocellular carcinoma (HCC) patients. Thus, identification of novel agents that can downregulate CXCR4 expression and its associated functions have a great potential in the treatment of metastatic HCC. In the present report, we investigated an anthraquinone derivative, emodin for its ability to affect CXCR4 expression as well as function in HCC cells. We observed that emodin downregulated the expression of CXCR4 in a dose-and time-dependent manner in HCC cells. Treatment with pharmacological proteasome and lysosomal inhibitors did not have substantial effect on emodin-induced decrease in CXCR4 expression. When investigated for the molecular mechanism(s), it was observed that the suppression of CXCR4 expression was due to downregulation of mRNA expression, inhibition of NF-κB activation, and abrogation of chromatin immunoprecipitation activity. Inhibition of CXCR4 expression by emodin further correlated with the suppression of CXCL12-induced migration and invasion in HCC cell lines. In addition, emodin treatment significantly suppressed metastasis to the lungs in an orthotopic HCC mice model and CXCR4 expression in tumor tissues. Overall, our results show that emodin exerts its anti-metastatic effect through the downregulation of CXCR4 expression and thus has the potential for the treatment of HCC.
Background. The objective of this prospective study was to evaluate the clinical profile, microbiological flora and radiological features in primary atrophic rhinitis patients and to identify their association with the etiology of primary atrophic rhinitis. Study design. Prospective case study. Materials and methods. Patients with primary atrophic rhinitis over a two years period were included in the study. Complete blood count, total protein and microbiological analysis from nasal swab were done to evaluate iron deficiency anemia, nutritional status and identification of the pathogenic bacteria respectively. Radiological evaluation was done to study the radiological features of primary atrophic rhinitis.
Observations. Ninety cases of primary atrophic rhinitis were studied. The most common symptom was nasal crusting. Nasal crust, odour and atrophy of mucosa were the most consistent finding. Nasal myiasis was found in 26.6% cases. The nasal mucociliary clearance time was markedly increased. On investigation there were low value of hemoglobin and total protein in 46.6% and 25.5% patients, respectively. Pseudomonas aeruginosa (37%) was the commonest organism isolated from culture. On radiological evaluation evidence of different grade of sinusitis was seen in 87.7% case.
Conclusion. The present study suggested that certain bacterial infections, anemia, poor nutrition and hereditary factor may contribute significantly to the etiology of primary atrophic rhinitis.
DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified by a fragment-based lead generation (FBLG) approach using nuclear magnetic resonance (NMR) screening to identify low-molecular-weight compounds that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding constant of 1 mM formed the basis of the design and synthesis of a focused library of compounds that resulted in the rapid identification of a lead compound that inhibited DNA gyrase with a 50% inhibitory concentration (IC50) of 3 μM. The potency of the lead compound was further optimized by utilizing iterative X-ray crystallography to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates containing pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compounds was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clinical indications.
Trypanosoma cruzi, a blood-borne parasite, is the etiological agent of Chagas disease. T. cruzi trypomastigotes, the infectious life cycle stage, can be detected in blood of infected individuals using PCR-based methods. However, soon after a natural infection, or during the chronic phase of Chagas disease, the number of parasites in blood may be very low and thus difficult to detect by PCR. To facilitate PCR-based detection methods, a parasite concentration approach was explored. A whole cell SELEX strategy was utilized to develop serum stable RNA aptamers that bind to live T. cruzi trypomastigotes. These aptamers bound to the parasite with high affinities (8–25 nM range). The highest affinity aptamer, Apt68, also demonstrated high specificity as it did not interact with the insect stage epimastigotes of T. cruzi nor with other related trypanosomatid parasites, L. donovani and T. brucei, suggesting that the target of Apt68 was expressed only on T. cruzi trypomastigotes. Biotinylated Apt68, immobilized on a solid phase, was able to capture live parasites. These captured parasites were visible microscopically, as large motile aggregates, formed when the aptamer coated paramagnetic beads bound to the surface of the trypomastigotes. Additionally, Apt68 was also able to capture and aggregate trypomastigotes from several isolates of the two major genotypes of the parasite. Using a magnet, these parasite-bead aggregates could be purified from parasite-spiked whole blood samples, even at concentrations as low as 5 parasites in 15 ml of whole blood, as detected by a real-time PCR assay. Our results show that aptamers can be used as pathogen specific ligands to capture and facilitate PCR-based detection of T. cruzi in blood.
Otolaryngology, although considered a surgical specialty, also covers many diseases that are not cured by surgery. These are treated medically and thus the otolaryngologist should have a good knowledge of drug treatments. It also entails ability to recognize, when an ENT symptom may be caused by one of the patient’s medications, particularly as this is easily remedied by changing the drug. Although most of us know the common drugs that can cause otological side effects, there are many others that we may not be aware of. Here we have tried to consolidate a list of some commonly used drugs having otological side effects.
Ototoxicity; Ototoxic drugs; Hearing loss
Advanced cancer patients are managed by palliative care and its main aim is to provide best possible quality of life to the patients by symptom management. Pain is the most agonizing symptom experienced by advanced head and neck cancer patients. Control of pain hence requires more attention by the caregiver in order to improve their quality of life. Recently quality of life issues have emerged as a main focus of cancer treatment as compared to conventional increase in survival rate. This study mainly focuses on the effect of palliative drug therapy on quality of life.
Advanced head and neck cancer; Quality of life; Palliative drug therapy
The purpose of this study was to classify various types of non-neoplastic and neoplastic lesions presenting as sinonasal mass and characterize their clinico-pathological profile in a tertiary care center in the state of Uttarakhand.
Materials and Methods:
This was a prospective study where 110 cases of sinonasal masses were included over a period of 12 months. Clinico-pathological study was carried out in these cases. A provisional diagnosis was made after clinical assessment and radiologic investigations, but final diagnosis was made after histopathologic examination.
The number of non-neoplastic lesions were more than the neoplastic lesion, 60% versus 40% respectively. In the neoplastic group, 19.8% and 23.76% patients presented with benign and malignant lesion, respectively. The incidence was more predominant in the age group of 11-20 years (22.72%) with male to female ratio of 1.08:1. In our study, among non-neoplastic lesions the occurrence of sinonasal polyps was highest seen in 80.30% cases. In neoplastic lesions, angiofibroma was most common benign lesion seen in 35% cases. Carcinoma nasal cavity was the commonest malignant lesion seen in 45.83% cases. In 3.63% patients, clinical and radiologic diagnosis was not correlated with histopathologic diagnosis. Only two cases required immuno-histocytochemistry to confirm the final diagnosis.
We concluded that for proper evaluation of a sinonasal mass, clinical, radiologic, and histopathologic evaluation should be carried out conjointly in all the cases. Histopathology always gives a confirmatory diagnosis but in few cases immuno-histocytochemistry becomes the ultimate diagnostic technique for correct and timely intervention.
Histopathology; neoplastic lesion; sinonasal mass
Primary atrophic rhinitis is a progressive chronic nasal disease and histopathologically characterized by squamous metaplasia and two characteristic types of vascular involvement (type I and type II). Despite its chronicity and squamous transformation, nothing is known about the occurrence of malignancy in atrophic rhinitis. The present work was undertaken to study the histopathological characteristics in primary atrophic rhinitis and identify whether it has any association with malignant transformation. Nasal biopsies obtained from 90 patients diagnosed as primary atrophic rhinitis were studied. Squamous metaplasia was noted in 89% of patients, and type I and type II vascular involvement were seen in 67% and 33% of patients, respectively. This preliminary report suggests that there is no association between atrophic rhinitis and precancerous lesions of nasal cavity despite squamous metaplasia and confirms the presence of two types of vascular changes in the disease which is helpful to decide the treatment modality.
Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.
Gout; hyperuricemia; xanthine oxidase inhibitor
This study was conducted to find out the status of the ossicles in cases of chronic suppurative otitis media (CSOM). One hundred and fifty cases of CSOM, who underwent surgery, were included and their intra-operative ossicular chain findings noted. Ossicular erosion was found to be much more common in unsafe CSOM than in safe CSOM. Malleus was found to be the most resistant ossicle to erosion whereas incus was found to be the most susceptible.
Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis.
In this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays.
We found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells.
Overall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer.
Management of anterior skull base tumors is complex due to the anatomic detail of the region and the variety of tumors that occur in this area. Currently, the “gold standard” for surgery is the anterior craniofacial approach. Craniofacial resection represents a major advance in the surgical treatment of tumors of the paranasal sinuses involving anterior skull base. It allows wide exposure of the complex anatomical structures at the base of skull permitting monobloc tumor resection. This study presents a series of 18 patients with anterior skull base tumors, treated by a team of head-neck surgeons and neurosurgeons. The series included 15 malignant tumors of the nose and paranasal sinuses and 3 extensive benign lesions. All tumors were resected by a combined bi-frontal craniotomy and rhinotomy. The skull base was closed with a pediculated pericranial flap and a split-thickness free skin graft underneath. There were no postoperative problems of wound infection, cerebrospinal fluid-leakage or meningitis. Recurrent tumor growth or systemic metastasis occurred in 3 out of 15 patients with malignant tumors, 6 months to 2 years postoperatively. Craniofacial resection was thus found to give excellent results with low morbidity in malignant lesions and can also be adapted for benign tumors of anterior skull base.
Craniofacial approach; Anterior skull base tumor