This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follow... more This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To assess the accuracy of the four-symptom screen (cough, fever, night sweats, or weight loss) for identifying active TB in pregnant PLHIV who are screened in an outpatient or community setting. To investigate potential sources of heterogeneity of the accuracy of the four-symptom screen between studies including: ART status, CD4 cell count, gestational age, pregnancy stage (pregnancy vs. postpartum), screening test definition of cough (any cough vs. cough greater than 2 weeks).To describe the accuracy of single symptoms included within the four-symptom screen, additioal symptoms or symptom combinations, for identifying active TB in pregnant PLHIV. For example, additional symptoms may include failure to gain weight or fatigue.
Mitochondrial oxidative-phosphorylation produces most of the energy in aerobic cells by coupling ... more Mitochondrial oxidative-phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton-gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as promising targets for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial-membrane-potential (MMP) in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol, but not cyclosporin A, and were non-existent in mitochondrial-DNA depleted HepG2 (po) cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreases MMP...
4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has ... more 4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal ...
Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug tri... more Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. Of 1205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
Chemical science (Royal Society of Chemistry : 2010)
Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent ... more Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure-activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral adm...
Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malign... more Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.
Kidney cancer, also known as renal cell carcinoma (RCC), is one of the top 10 diagnosed cancers i... more Kidney cancer, also known as renal cell carcinoma (RCC), is one of the top 10 diagnosed cancers in the USA, and the incidence is rising. Despite major improvements in drug therapy strategies, RCC remains a deadly malignancy if not found and removed in its early stages. RCC is so highly drug-resistant that no effective life-prolonging regimen of cytotoxic chemotherapy has been demonstrated for RCC, despite several decades of effort. It is also highly radiation-resistant, thus circumventing therapies to prevent local recurrence or to control metastatic disease. In the last few years, extensive research has been conducted to elucidate the functional significance of the plant-derived compounds, and their derivatives, as anticancer agents. This review is focussed on a chemo-dietary prevention strategy against RCC using a citrus-derived compound called 2'-hydroxyflavanone. RCC is frequently caused by VHL gene mutations, which contribute to 75% of all RCCs. These mutations are positively linked to cigarette smoking, and exposure to the tobacco carcinogen, N-nitrosodimethylamine and benzopyrene, can disrupt VHL. According to in vitro and preclinical mouse studies, 2'-hydroxyflavanone can both protect the VHL locus and prevent the progression of VHL-mutant cancer. Human clinical trials examining the effect of supplementation of 2'-hydroxyflavanone, either alone or in combination with chemotherapeutic drugs, on RCC prevention have not been conducted, although there is considerable potential for 2'-hydroxyflavanone and its derivatives to be developed as RCC chemoprevention agents. Therefore, the discovery of plant-derived cancer therapies, such as 2'-hydroxyflavanone, offers a new strategy for combating this highly resistant cancer.
Background: Maternal HIV/TB co-infection is associated with poor maternal and infant outcomes. Pr... more Background: Maternal HIV/TB co-infection is associated with poor maternal and infant outcomes. Pregnancy provides a unique opportunity for TB screening and isoniazid preventative therapy. Our study objective is to determine prevalence and cofactors of active and latent TB infection (LTBI) and to evaluate performance of the WHO TB symptom screen and sputum Xpert for diagnosis/exclusion of active TB among pregnant HIV-infected women in Western Kenya. Methods: This is an ongoing cross-sectional study of HIV-infected pregnant women in two maternal child health clinics in Nyanza Province, Kenya. All enrolled women undergo WHO TB symptom screening. Two sputum specimens are collected for smear and liquid culture, and one for Xpert performed at the CDC-KEMRI lab. Active TB was defined by at least one positive culture. Women with positive tuberculin skin test and negative culture were considered to have LTBI. Smear and Xpert were compared to the gold-standard of culture. Results: Between Jul...
World journal for pediatric & congenital heart surgery, 2012
Pediatric extracorporeal membrane oxygenation (ECMO) programs are sophisticated endeavors usually... more Pediatric extracorporeal membrane oxygenation (ECMO) programs are sophisticated endeavors usually found only in high-volume cardiac surgical programs. Worldwide, many cardiology programs do not have on-site pediatric cardiac surgery expertise. Our single-center experience shows that an organized multidisciplinary rescue-ECMO program, in collaboration with an accepting facility, can achieve survival rates comparable to modern era on-site ECMO. A retrospective review was conducted of all patients initiated on rescue-ECMO from 2004 to 2009 in a single academic pediatric hospital without a pediatric cardiac surgery program. All aspects of ECMO were formalized using Failure Mode Effects Analysis. Eight patients were initially cannulated for ECMO at our institution. Six were subsequently transported by air to the receiving facility 1,305 km away. Extracorporeal membrane oxygenation was initiated in 0.2% of our Pediatric Intensive Care Unit admissions and in 0.52% of all our pediatric card...
Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection ... more Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p < 0.05) while three additional SNPs neared significance (0.05 < p < 0.1). When these six SNPs were evaluated in a validation cohort (n = 339 cases, 367 controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p = 0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p = 0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis.
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer a... more JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role o...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 22, 2014
Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth ... more Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth and survival. In this study, we developed a simple and efficient method to radiolabel neurotensin peptide with (18)F for NTR-targeted imaging. The thiol-reactive reagent (18)F-(2-(2-(2-fluoroethoxy)ethoxy)ethylsulfonyl)ethane ((18)F-DEG-VS) was facilely prepared through 1-step radiofluorination. After high-pressure liquid chromatography purification, (18)F-DEG-VS was incubated with the c(RGDyC) and c(RGDyK) peptide mixture to evaluate its specificity toward the reactive thiol. Thiolated neurotensin peptide was then labeled with (18)F using this novel synthon, and the resulting imaging probe was subjected to receptor-binding assay and small-animal PET studies in a murine xenograft model. The imaging results and metabolic stability of (18)F-DEG-VS-NT were compared with the thiol-specific maleimide derivative N-[2-(4-(18)F-fluorobenzamido)ethyl]maleimide-neurotensin ((18)F-FBEM-NT). (18)F-D...
This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follow... more This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To assess the accuracy of the four-symptom screen (cough, fever, night sweats, or weight loss) for identifying active TB in pregnant PLHIV who are screened in an outpatient or community setting. To investigate potential sources of heterogeneity of the accuracy of the four-symptom screen between studies including: ART status, CD4 cell count, gestational age, pregnancy stage (pregnancy vs. postpartum), screening test definition of cough (any cough vs. cough greater than 2 weeks).To describe the accuracy of single symptoms included within the four-symptom screen, additioal symptoms or symptom combinations, for identifying active TB in pregnant PLHIV. For example, additional symptoms may include failure to gain weight or fatigue.
Mitochondrial oxidative-phosphorylation produces most of the energy in aerobic cells by coupling ... more Mitochondrial oxidative-phosphorylation produces most of the energy in aerobic cells by coupling respiration to the production of ATP. Mitochondrial uncouplers, which reduce the proton-gradient across the mitochondrial inner membrane, create a futile cycle of nutrient oxidation without generating ATP. Regulation of mitochondrial dysfunction and associated cellular bioenergetics has been recently identified as promising targets for anticancer therapy. Here, we show that SR4 is a novel mitochondrial uncoupler that causes dose-dependent increase in mitochondrial respiration and dissipation of mitochondrial-membrane-potential (MMP) in HepG2 hepatocarcinoma cells. These effects were reversed by the recoupling agent 6-ketocholestanol, but not cyclosporin A, and were non-existent in mitochondrial-DNA depleted HepG2 (po) cells. In isolated mouse liver mitochondria, SR4 similarly increased oxygen consumption independent of adenine nucleotide translocase and uncoupling proteins, decreases MMP...
4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has ... more 4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal ...
Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug tri... more Wheeze is an important sign indicating a potentially severe adverse event in vaccine and drug trials, particularly in children. However, there are currently no consensus definitions of wheeze or associated respiratory compromise in randomized controlled trials (RCTs). To identify definitions and severity grading scales of wheeze as an adverse event in vaccine and drug RCTs enrolling children <5 years and to determine their diagnostic performance based on sensitivity, specificity and inter-observer agreement. We performed a systematic review of electronic databases and reference lists with restrictions for trial settings, English language and publication date ≥1970. Wheeze definitions and severity grading were abstracted and ranked by a diagnostic certainty score based on sensitivity, specificity and inter-observer agreement. Of 1205 articles identified using our broad search terms, we identified 58 eligible trials conducted in 38 countries, mainly in high-income settings. Vaccines made up the majority (90%) of interventions, particularly influenza vaccines (65%). Only 15 trials provided explicit definitions of wheeze. Of 24 studies that described severity, 11 described wheeze severity in the context of an explicit wheeze definition. The remaining 13 studies described wheeze severity where wheeze was defined as part of a respiratory illness or a wheeze equivalent. Wheeze descriptions were elicited from caregiver reports (14%), physical examination by a health worker (45%) or a combination (41%). There were 21/58 studies in which wheeze definitions included combined caregiver report and healthcare worker assessment. The use of these two methods appeared to have the highest combined sensitivity and specificity. Standardized wheeze definitions and severity grading scales for use in pediatric vaccine or drug trials are lacking. Standardized definitions of wheeze are needed for assessment of possible adverse events as new vaccines and drugs are evaluated.
Chemical science (Royal Society of Chemistry : 2010)
Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent ... more Epipolythiodioxopiperazine (ETP) alkaloids are structurally elaborate alkaloids that show potent antitumor activity. However, their high toxicity and demonstrated interactions with various biological receptors compromises their therapeutic potential. In an effort to mitigate these disadvantages, a short stereocontrolled construction of tricyclic analogues of epidithiodioxopiperazine alkaloids was developed. Evaluation of a small library of such structures against two invasive cancer cell lines defined initial structure-activity relationships (SAR), which identified 1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine 3c and related structures as particularly promising antitumor agents. ETP alkaloid analogue 3c exhibits low nanomolar activity against both solid and blood tumors in vitro. In addition, 3c significantly suppresses tumor growth in mouse xenograft models of melanoma and lung cancer, without obvious signs of toxicity, following either intraperitoneal (IP) or oral adm...
Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malign... more Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.
Kidney cancer, also known as renal cell carcinoma (RCC), is one of the top 10 diagnosed cancers i... more Kidney cancer, also known as renal cell carcinoma (RCC), is one of the top 10 diagnosed cancers in the USA, and the incidence is rising. Despite major improvements in drug therapy strategies, RCC remains a deadly malignancy if not found and removed in its early stages. RCC is so highly drug-resistant that no effective life-prolonging regimen of cytotoxic chemotherapy has been demonstrated for RCC, despite several decades of effort. It is also highly radiation-resistant, thus circumventing therapies to prevent local recurrence or to control metastatic disease. In the last few years, extensive research has been conducted to elucidate the functional significance of the plant-derived compounds, and their derivatives, as anticancer agents. This review is focussed on a chemo-dietary prevention strategy against RCC using a citrus-derived compound called 2'-hydroxyflavanone. RCC is frequently caused by VHL gene mutations, which contribute to 75% of all RCCs. These mutations are positively linked to cigarette smoking, and exposure to the tobacco carcinogen, N-nitrosodimethylamine and benzopyrene, can disrupt VHL. According to in vitro and preclinical mouse studies, 2'-hydroxyflavanone can both protect the VHL locus and prevent the progression of VHL-mutant cancer. Human clinical trials examining the effect of supplementation of 2'-hydroxyflavanone, either alone or in combination with chemotherapeutic drugs, on RCC prevention have not been conducted, although there is considerable potential for 2'-hydroxyflavanone and its derivatives to be developed as RCC chemoprevention agents. Therefore, the discovery of plant-derived cancer therapies, such as 2'-hydroxyflavanone, offers a new strategy for combating this highly resistant cancer.
Background: Maternal HIV/TB co-infection is associated with poor maternal and infant outcomes. Pr... more Background: Maternal HIV/TB co-infection is associated with poor maternal and infant outcomes. Pregnancy provides a unique opportunity for TB screening and isoniazid preventative therapy. Our study objective is to determine prevalence and cofactors of active and latent TB infection (LTBI) and to evaluate performance of the WHO TB symptom screen and sputum Xpert for diagnosis/exclusion of active TB among pregnant HIV-infected women in Western Kenya. Methods: This is an ongoing cross-sectional study of HIV-infected pregnant women in two maternal child health clinics in Nyanza Province, Kenya. All enrolled women undergo WHO TB symptom screening. Two sputum specimens are collected for smear and liquid culture, and one for Xpert performed at the CDC-KEMRI lab. Active TB was defined by at least one positive culture. Women with positive tuberculin skin test and negative culture were considered to have LTBI. Smear and Xpert were compared to the gold-standard of culture. Results: Between Jul...
World journal for pediatric & congenital heart surgery, 2012
Pediatric extracorporeal membrane oxygenation (ECMO) programs are sophisticated endeavors usually... more Pediatric extracorporeal membrane oxygenation (ECMO) programs are sophisticated endeavors usually found only in high-volume cardiac surgical programs. Worldwide, many cardiology programs do not have on-site pediatric cardiac surgery expertise. Our single-center experience shows that an organized multidisciplinary rescue-ECMO program, in collaboration with an accepting facility, can achieve survival rates comparable to modern era on-site ECMO. A retrospective review was conducted of all patients initiated on rescue-ECMO from 2004 to 2009 in a single academic pediatric hospital without a pediatric cardiac surgery program. All aspects of ECMO were formalized using Failure Mode Effects Analysis. Eight patients were initially cannulated for ECMO at our institution. Six were subsequently transported by air to the receiving facility 1,305 km away. Extracorporeal membrane oxygenation was initiated in 0.2% of our Pediatric Intensive Care Unit admissions and in 0.52% of all our pediatric card...
Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection ... more Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p < 0.05) while three additional SNPs neared significance (0.05 < p < 0.1). When these six SNPs were evaluated in a validation cohort (n = 339 cases, 367 controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p = 0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p = 0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis.
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer a... more JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in patients with ovarian cancer. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late-stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine cytokine loop involving the IL6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination, and diminished ascites production, suggesting a critical role o...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 22, 2014
Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth ... more Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth and survival. In this study, we developed a simple and efficient method to radiolabel neurotensin peptide with (18)F for NTR-targeted imaging. The thiol-reactive reagent (18)F-(2-(2-(2-fluoroethoxy)ethoxy)ethylsulfonyl)ethane ((18)F-DEG-VS) was facilely prepared through 1-step radiofluorination. After high-pressure liquid chromatography purification, (18)F-DEG-VS was incubated with the c(RGDyC) and c(RGDyK) peptide mixture to evaluate its specificity toward the reactive thiol. Thiolated neurotensin peptide was then labeled with (18)F using this novel synthon, and the resulting imaging probe was subjected to receptor-binding assay and small-animal PET studies in a murine xenograft model. The imaging results and metabolic stability of (18)F-DEG-VS-NT were compared with the thiol-specific maleimide derivative N-[2-(4-(18)F-fluorobenzamido)ethyl]maleimide-neurotensin ((18)F-FBEM-NT). (18)F-D...
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