Nicholas Larsen - Academia.edu (original) (raw)

Papers by Nicholas Larsen

Clinical Autonomic Research, 2022

As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic ... more As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic complications are being recognized with increasing frequency in both the acute and chronic form of the illness, the latter now designated as post-acute sequelae of SARS-CoV-2 (PASC), colloquially termed long-COVID. Tachycardia is a common symptom of PASC, and some patients may be diagnosed with postural tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST). While post-COVID POTS has garnered more attention from the scientific and popular press, IST may be equally or more common and has been reported in survivors of the prior SARS coronavirus pandemic [1]. The etiology of IST is unknown; however, the proposed mechanisms overlap with those of POTS, including increased sympathetic and/or reduced cardiovagal activity. In their recent publication [2], “Inappropriate sinus tachycardia in post-COVID-19 syndrome” Aranyo and colleagues identified 200 consecutive patients with PASC....

Clinical Autonomic Research

Clinical Autonomic Research

The Institute of Food and Agricultural Sciences (IFAS) is an Equal Opportunity Institution author... more The Institute of Food and Agricultural Sciences (IFAS) is an Equal Opportunity Institution authorized to provide research, educational information and other services only to individuals and institutions that function with non-discrimination with respect to race, creed, color, religion, age, disability, sex, sexual orientation, marital status, national origin, political opinions or affiliations.

Nutrient leaching is a necessary, but wasteful part of growing nursery plants. Substrate, fertili... more Nutrient leaching is a necessary, but wasteful part of growing nursery plants. Substrate, fertilization, and their interactions affect nutrient leaching. This study was designed to investigate nutrient leaching from tissue culture bananas during the acclimation phase in four different substrates. The growing media mixtures consisted of 90% and 55% sugarcane filter press mud (FP) or sphagnum peat (SP) by volume mixed equal parts of perlite and vermiculite to make up the complement of each mixture. There were 3 fertilization treatments: Osmocote Plus 15–9–12, 3–4 month release incorporated at the rates of 2.4 g/L, 4.8 g/L and 7.2 g/L. The experiment was designed as a completely randomized design factorial with each media x fertilization treatment consisting of three replicates for a total of 36 experimental units. Nitrate leaching was higher in FP treatments. Ammonium leaching was higher in SP treatments. Phosphorus leaching was higher in SP treatments. The lowest level of fertilizati...

SSRN Electronic Journal

Compared to other immigrants to the United States, recent Jewish immigrants from the former Sovie... more Compared to other immigrants to the United States, recent Jewish immigrants from the former Soviet Union have achieved high levels of English language proficiency and earnings. They experience disadvantages in both dimensions at arrival, but because of steeper improvements with duration in the United States, they reach parity or surpass the English proficiency and earnings of other immigrants. This pattern is seen in the most recent data, the American Community Survey, 2005 to 2009, which is studied here, but also in earlier censuses (1980-2000). The Russian Jews, whether male or female, have higher levels of schooling and English proficiency. Moreover, they appear to secure greater earnings payoffs in the US labor market from their schooling, their labor market experience in the US, and their proficiency in English. What is perhaps remarkable is that the Russian Jewish immigrants from the late 19th and early 20th centuries (1881 to 1920's) also experienced high levels of human capital accumulation and economic success (measured by earnings or occupational attainment). And their US-born children achieved even greater successes compared to other native-born children. This is not emerging from a highly selective immigrant population. The Russian Jewish migration is a mass migration influenced, in part, by refugee motivations. This leads to the obvious but still unanswered question: What is it about the Jews of the Former Russian Empire/Soviet Union that has resulted in their high levels of success in the United States over the past 25 years?

Background: Lung cancer is one of the most common malignances with an ever-increasing incidence a... more Background: Lung cancer is one of the most common malignances with an ever-increasing incidence and high mortality. The insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as RNA-binding proteins play an important role in messenger RNA (mRNA) regulation during tumor development. Even so, the expression and prognostic values of IGF2BPs in lung cancer have not been clarified.Main methods: To address this issue, the study investigated the roles of IGF2BPs in the prognosis of lung cancer by using public databases and quantitative real-time PCR (Q-PCR).Results: The transcriptional levels of IGF2BP1/2/3 in lung cancer tissues were significantly elevated, associating with pathological stages and poor prognosis of overall survival (OS) and progression-free survival (FP) in lung cancer patients. A high mutation rate of IGF2BPs (24%) was also observed of patients with lung cancer. The functions of differentially expressed IGF2BPs are primarily related to the spliceosome, hippo signal...

Cureus

Lung cancer still remains one of the most common cancers throughout the world, especially in smok... more Lung cancer still remains one of the most common cancers throughout the world, especially in smokers. Adenocarcinoma is now the predominant histological type in many western countries. The etiology of adenocarcinoma is unknown, but evidence suggests that atypical adenomatous hyperplasia (AAH) may act as a precursor lesion. Here we present two case reports of patients diagnosed with AAH on biopsy, highlighting 1) available treatment strategies and 2) AAH's progression to adenocarcinoma. A review of AAH is warranted as little literature is currently available regarding its treatment strategies, especially in light of its role as a precursor to adenocarcinoma. In this review, we will address the following topics: 1. What is the pathophysiology of AAH? 2. What is the natural history of AAH and its risk of malignant transformation? 3. When is surgery recommended? 4. What is the role of stereotactic body radiotherapy (SBRT) in the rare patient who refuses surgery?

Nature Communications

The original version of this Article contained an error in the spelling of the author Htoo Zarni ... more The original version of this Article contained an error in the spelling of the author Htoo Zarni Oo, which was incorrectly given as Htoo Z. Oo. This has now been corrected in both the PDF and HTML versions of the Article.

Bioorganic & medicinal chemistry letters, May 1, 2018

The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinas... more The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).

Genes & development, Feb 1, 2018

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 and PHF5A The structure suggests a model in which splicing modulators interfere with branch poin...

Cancer Research

Hepatocellular carcinoma (HCC) has limited treatment options and generally poor prognosis. Recent... more Hepatocellular carcinoma (HCC) has limited treatment options and generally poor prognosis. Recent genomic studies have identified FGF19 as a driver oncogene in HCC. FGF19 is a gut secreted hormone that acts in the liver through FGFR4 to regulate bile acid synthesis. Consistent with the notion that FGF19 is a driver oncogene in HCC, transgenic mice overexpressing FGF19 form liver tumors and genetic ablation of FGFR4 prevented tumor formation. These data suggest targeting FGFR4 would have therapeutic benefit in HCC with altered FGF19 signaling. While a number of Pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by their FGFR1-3 related dose limiting toxicities. Using structure guided drug design, we have generated a highly selective covalent FGFR4 inhibitor, H3B-6527. Biochemical and cellular selectivity assays showed that H3B-6527 is >300 fold selective towards FGFR4 compared to other FGFR isoforms. Addition of H3B-6527 to FGF19 amplified HCC cell lines led to dose dependent inhibition of FGF19/FGFR4 signaling and concomitant reduction in cell viability. In a panel of 40 HCC cell lines, H3B-6527 selectively reduced the viability of cells that harbor FGF19 amplification and showed no effect in FGF19 non-amplified HCC cell line models. Oral dosing of H3B-6527 to mice led to dose-dependent pharmacodynamic modulation of FGFR4 signaling and tumor regression in FGF19 altered HCC cell line derived xenograft models. H3B-6527 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC grown in nude mice. Importantly, the inhibition of tumor growth occurred at doses that were well tolerated in mice and no evidence of FGFR1-3 related toxicities were observed at efficacious doses. In a panel of 30 HCC patient-derived xenograft (PDX) models, H3B-6527 demonstrated tumor regressions in the context of FGF19-amplified tumors. In addition, H3B-6527 showed antitumor activity and tumor regressions in PDX models with high FGF19 expression but no FGF19 amplification. The mechanism for FGF19 overexpression in the absence of gene amplification is under investigation. In conclusion, our preclinical studies demonstrate that FGF19 expression is a predictive biomarker for response to FGFR4 inhibitor therapy. Genomic analysis of public and proprietary data sets indicates that at least approximately 30% of HCC patients exhibit altered FGF19 expression and could potentially benefit from H3B-6527 monotherapy treatment. Citation Format: Anand Selvaraj, Erik Corcoran, Heather Coffey, Sudeep Prajapati, Ming-Hong Hao, Nicholas Larsen, Jennifer Tsai, Takashi Satoh, Kana Ichikawa, Julie Jaya Joshi, Raelene Hurley, Jeremy Wu, Chia-Ling Huang, Suzanna Bailey, Craig Karr, Pavan Kumar, Victoria Rimkunas, Crystal Mackenzie, Nathalie Rioux, Amy Kim, Sandeep Akare, George Lai, Lihua Yu, Peter Fekkes, John Wang, Markus Warmuth, Peter Smith, Dominic Reynolds. H3B6527, a selective and potent FGFR4 inhibitor for FGF19-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3126. doi:10.1158/1538-7445.AM2017-3126

Florida Entomologist

BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access t... more BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.

Nature communications, Jul 24, 2017

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. ... more Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ(High)/RXRα(S427F/Y) impairs CD8(+) T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokin...

Arthropod Management Tests, 2016

Hosts: Corn (hybrid, maize, sweet) j Zea mays Pests: Euxesta stigmatias (Loew) Euxesta eluta (Loe... more Hosts: Corn (hybrid, maize, sweet) j Zea mays Pests: Euxesta stigmatias (Loew) Euxesta eluta (Loew) Chaetopsis massyla (Walker) Fall armyworm (FAW) j Spodoptera frugiperda (J. E. Smith) Fresh market sweet corn grown in Southern Florida requires frequent insecticide applications to prevent ear damage by picture-winged flies (Diptera: Ulidiidae, Euxesta spp., Chaetopsis spp.) and fall armyworm (FAW). Pyrethroid rotation efficacy was compared with a reduced-risk insecticide mixed with a protein feeding stimulant to evaluate insect damage to harvested ears. Three 20-row blocks of var. 'Obsession' sweet corn were planted on 76.2 cm (30 in.) beds at the Everglades Research and Education Center, Belle Glade, FL on 16 Sept using a John Deere Max Emerge 4-row vacuum planter. Seeds were spaced 20.3 cm (8 in.) apart. Whorl feeding FAW were treated with Coragen and Rimon on 5 and 14 Oct, respectively. Unplanted 4.6 m (15 ft.) alleys separated blocks, and 3.0 m (10 ft.) alleys separated treatments within blocks. Each treatment plot was 45.7 m (150 ft.) long. An RCB design was used with three replicates per treatment. Insecticide treatments targeting ulidiid flies were initiated on 26 Oct at first silk. The first treatment (Pyrethroid) consisted of a sequential pyrethroid rotation among Baythroid XL, Warrior II, and

Arthropod Management Tests, 2016

The Journal of Developing Areas, 2016

Research on the efficacy of foreign aid has been extensively conducted over the last three decade... more Research on the efficacy of foreign aid has been extensively conducted over the last three decades, but empirically the results remain inconclusive. Previous literature has relied upon linear growth model to estimate their models, methods inconsistent with the existence of poverty traps. These approaches have found that the effect of foreign is either negative, to positive, or even conditional on the policy environment in the country. More recent theoretical literature has started to point towards a nonlinear effect of foreign aid on the level of income. This nonlinear effect is consistent with a poverty trap model. To provide empirical support for this theory this paper relaxes the assumption of linearity in the model to determine if the efficacy of foreign aid is nonlinear. To accomplish this the relationship between foreign aid and the level of income is examined using a cross sectional data set of 72 countries that received Official Development Aid between 1985 and 2014 using a multivariate adaptive regressive splines (MARS) estimation. The MARS model is a nonlinear approach that systematically identifies both threshold levels and interaction terms between independent variables. Most importantly, the MARS model will detect if foreign aid has a statistically significant threshold effect. This finding would be consistent with the poverty trap hypothesis and also explain why there has been a lack of consensus so far. The results suggest that by using a nonlinear estimation we significantly improve, 18 to 44 percent reduction in the residual sum of squares, the fit of our growth model compared to an ordinary least squares estimation, as well as also detect a threshold in the effect of foreign aid that is consistent with a poverty trap hypothesis. These results are consistent when we analyze foreign aid as either a percent of gross national income—threshold at 4.6 percent—or per capita—threshold at $24.97. Below these thresholds the effect of foreign aid is either negative, or statistically zero, but when foreign aid is sufficiently large the effect is large and positive. We also detect significant interactions between foreign aid and both human capital and population growth. The policy implication being that if a country is going to experience a positive impact on their level of income the amount of foreign aid needs to be sufficiently large enough. Furthermore, the interactions suggest that some degree of selectivity should take place on which countries are best equipped to use aid.

Clinical Autonomic Research, 2022

As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic ... more As the COVID-19 pandemic continues to affect hundreds of millions of people worldwide, autonomic complications are being recognized with increasing frequency in both the acute and chronic form of the illness, the latter now designated as post-acute sequelae of SARS-CoV-2 (PASC), colloquially termed long-COVID. Tachycardia is a common symptom of PASC, and some patients may be diagnosed with postural tachycardia syndrome (POTS) or inappropriate sinus tachycardia (IST). While post-COVID POTS has garnered more attention from the scientific and popular press, IST may be equally or more common and has been reported in survivors of the prior SARS coronavirus pandemic [1]. The etiology of IST is unknown; however, the proposed mechanisms overlap with those of POTS, including increased sympathetic and/or reduced cardiovagal activity. In their recent publication [2], “Inappropriate sinus tachycardia in post-COVID-19 syndrome” Aranyo and colleagues identified 200 consecutive patients with PASC....

Clinical Autonomic Research

Clinical Autonomic Research

The Institute of Food and Agricultural Sciences (IFAS) is an Equal Opportunity Institution author... more The Institute of Food and Agricultural Sciences (IFAS) is an Equal Opportunity Institution authorized to provide research, educational information and other services only to individuals and institutions that function with non-discrimination with respect to race, creed, color, religion, age, disability, sex, sexual orientation, marital status, national origin, political opinions or affiliations.

Nutrient leaching is a necessary, but wasteful part of growing nursery plants. Substrate, fertili... more Nutrient leaching is a necessary, but wasteful part of growing nursery plants. Substrate, fertilization, and their interactions affect nutrient leaching. This study was designed to investigate nutrient leaching from tissue culture bananas during the acclimation phase in four different substrates. The growing media mixtures consisted of 90% and 55% sugarcane filter press mud (FP) or sphagnum peat (SP) by volume mixed equal parts of perlite and vermiculite to make up the complement of each mixture. There were 3 fertilization treatments: Osmocote Plus 15–9–12, 3–4 month release incorporated at the rates of 2.4 g/L, 4.8 g/L and 7.2 g/L. The experiment was designed as a completely randomized design factorial with each media x fertilization treatment consisting of three replicates for a total of 36 experimental units. Nitrate leaching was higher in FP treatments. Ammonium leaching was higher in SP treatments. Phosphorus leaching was higher in SP treatments. The lowest level of fertilizati...

SSRN Electronic Journal

Compared to other immigrants to the United States, recent Jewish immigrants from the former Sovie... more Compared to other immigrants to the United States, recent Jewish immigrants from the former Soviet Union have achieved high levels of English language proficiency and earnings. They experience disadvantages in both dimensions at arrival, but because of steeper improvements with duration in the United States, they reach parity or surpass the English proficiency and earnings of other immigrants. This pattern is seen in the most recent data, the American Community Survey, 2005 to 2009, which is studied here, but also in earlier censuses (1980-2000). The Russian Jews, whether male or female, have higher levels of schooling and English proficiency. Moreover, they appear to secure greater earnings payoffs in the US labor market from their schooling, their labor market experience in the US, and their proficiency in English. What is perhaps remarkable is that the Russian Jewish immigrants from the late 19th and early 20th centuries (1881 to 1920's) also experienced high levels of human capital accumulation and economic success (measured by earnings or occupational attainment). And their US-born children achieved even greater successes compared to other native-born children. This is not emerging from a highly selective immigrant population. The Russian Jewish migration is a mass migration influenced, in part, by refugee motivations. This leads to the obvious but still unanswered question: What is it about the Jews of the Former Russian Empire/Soviet Union that has resulted in their high levels of success in the United States over the past 25 years?

Background: Lung cancer is one of the most common malignances with an ever-increasing incidence a... more Background: Lung cancer is one of the most common malignances with an ever-increasing incidence and high mortality. The insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as RNA-binding proteins play an important role in messenger RNA (mRNA) regulation during tumor development. Even so, the expression and prognostic values of IGF2BPs in lung cancer have not been clarified.Main methods: To address this issue, the study investigated the roles of IGF2BPs in the prognosis of lung cancer by using public databases and quantitative real-time PCR (Q-PCR).Results: The transcriptional levels of IGF2BP1/2/3 in lung cancer tissues were significantly elevated, associating with pathological stages and poor prognosis of overall survival (OS) and progression-free survival (FP) in lung cancer patients. A high mutation rate of IGF2BPs (24%) was also observed of patients with lung cancer. The functions of differentially expressed IGF2BPs are primarily related to the spliceosome, hippo signal...

Cureus

Lung cancer still remains one of the most common cancers throughout the world, especially in smok... more Lung cancer still remains one of the most common cancers throughout the world, especially in smokers. Adenocarcinoma is now the predominant histological type in many western countries. The etiology of adenocarcinoma is unknown, but evidence suggests that atypical adenomatous hyperplasia (AAH) may act as a precursor lesion. Here we present two case reports of patients diagnosed with AAH on biopsy, highlighting 1) available treatment strategies and 2) AAH's progression to adenocarcinoma. A review of AAH is warranted as little literature is currently available regarding its treatment strategies, especially in light of its role as a precursor to adenocarcinoma. In this review, we will address the following topics: 1. What is the pathophysiology of AAH? 2. What is the natural history of AAH and its risk of malignant transformation? 3. When is surgery recommended? 4. What is the role of stereotactic body radiotherapy (SBRT) in the rare patient who refuses surgery?

Nature Communications

The original version of this Article contained an error in the spelling of the author Htoo Zarni ... more The original version of this Article contained an error in the spelling of the author Htoo Zarni Oo, which was incorrectly given as Htoo Z. Oo. This has now been corrected in both the PDF and HTML versions of the Article.

Bioorganic & medicinal chemistry letters, May 1, 2018

The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinas... more The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).

Genes & development, Feb 1, 2018

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a... more Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1 and PHF5A The structure suggests a model in which splicing modulators interfere with branch poin...

Cancer Research

Hepatocellular carcinoma (HCC) has limited treatment options and generally poor prognosis. Recent... more Hepatocellular carcinoma (HCC) has limited treatment options and generally poor prognosis. Recent genomic studies have identified FGF19 as a driver oncogene in HCC. FGF19 is a gut secreted hormone that acts in the liver through FGFR4 to regulate bile acid synthesis. Consistent with the notion that FGF19 is a driver oncogene in HCC, transgenic mice overexpressing FGF19 form liver tumors and genetic ablation of FGFR4 prevented tumor formation. These data suggest targeting FGFR4 would have therapeutic benefit in HCC with altered FGF19 signaling. While a number of Pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by their FGFR1-3 related dose limiting toxicities. Using structure guided drug design, we have generated a highly selective covalent FGFR4 inhibitor, H3B-6527. Biochemical and cellular selectivity assays showed that H3B-6527 is >300 fold selective towards FGFR4 compared to other FGFR isoforms. Addition of H3B-6527 to FGF19 amplified HCC cell lines led to dose dependent inhibition of FGF19/FGFR4 signaling and concomitant reduction in cell viability. In a panel of 40 HCC cell lines, H3B-6527 selectively reduced the viability of cells that harbor FGF19 amplification and showed no effect in FGF19 non-amplified HCC cell line models. Oral dosing of H3B-6527 to mice led to dose-dependent pharmacodynamic modulation of FGFR4 signaling and tumor regression in FGF19 altered HCC cell line derived xenograft models. H3B-6527 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC grown in nude mice. Importantly, the inhibition of tumor growth occurred at doses that were well tolerated in mice and no evidence of FGFR1-3 related toxicities were observed at efficacious doses. In a panel of 30 HCC patient-derived xenograft (PDX) models, H3B-6527 demonstrated tumor regressions in the context of FGF19-amplified tumors. In addition, H3B-6527 showed antitumor activity and tumor regressions in PDX models with high FGF19 expression but no FGF19 amplification. The mechanism for FGF19 overexpression in the absence of gene amplification is under investigation. In conclusion, our preclinical studies demonstrate that FGF19 expression is a predictive biomarker for response to FGFR4 inhibitor therapy. Genomic analysis of public and proprietary data sets indicates that at least approximately 30% of HCC patients exhibit altered FGF19 expression and could potentially benefit from H3B-6527 monotherapy treatment. Citation Format: Anand Selvaraj, Erik Corcoran, Heather Coffey, Sudeep Prajapati, Ming-Hong Hao, Nicholas Larsen, Jennifer Tsai, Takashi Satoh, Kana Ichikawa, Julie Jaya Joshi, Raelene Hurley, Jeremy Wu, Chia-Ling Huang, Suzanna Bailey, Craig Karr, Pavan Kumar, Victoria Rimkunas, Crystal Mackenzie, Nathalie Rioux, Amy Kim, Sandeep Akare, George Lai, Lihua Yu, Peter Fekkes, John Wang, Markus Warmuth, Peter Smith, Dominic Reynolds. H3B6527, a selective and potent FGFR4 inhibitor for FGF19-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3126. doi:10.1158/1538-7445.AM2017-3126

Florida Entomologist

BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access t... more BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.

Nature communications, Jul 24, 2017

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. ... more Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ(High)/RXRα(S427F/Y) impairs CD8(+) T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokin...

Arthropod Management Tests, 2016

Hosts: Corn (hybrid, maize, sweet) j Zea mays Pests: Euxesta stigmatias (Loew) Euxesta eluta (Loe... more Hosts: Corn (hybrid, maize, sweet) j Zea mays Pests: Euxesta stigmatias (Loew) Euxesta eluta (Loew) Chaetopsis massyla (Walker) Fall armyworm (FAW) j Spodoptera frugiperda (J. E. Smith) Fresh market sweet corn grown in Southern Florida requires frequent insecticide applications to prevent ear damage by picture-winged flies (Diptera: Ulidiidae, Euxesta spp., Chaetopsis spp.) and fall armyworm (FAW). Pyrethroid rotation efficacy was compared with a reduced-risk insecticide mixed with a protein feeding stimulant to evaluate insect damage to harvested ears. Three 20-row blocks of var. 'Obsession' sweet corn were planted on 76.2 cm (30 in.) beds at the Everglades Research and Education Center, Belle Glade, FL on 16 Sept using a John Deere Max Emerge 4-row vacuum planter. Seeds were spaced 20.3 cm (8 in.) apart. Whorl feeding FAW were treated with Coragen and Rimon on 5 and 14 Oct, respectively. Unplanted 4.6 m (15 ft.) alleys separated blocks, and 3.0 m (10 ft.) alleys separated treatments within blocks. Each treatment plot was 45.7 m (150 ft.) long. An RCB design was used with three replicates per treatment. Insecticide treatments targeting ulidiid flies were initiated on 26 Oct at first silk. The first treatment (Pyrethroid) consisted of a sequential pyrethroid rotation among Baythroid XL, Warrior II, and

Arthropod Management Tests, 2016

The Journal of Developing Areas, 2016

Research on the efficacy of foreign aid has been extensively conducted over the last three decade... more Research on the efficacy of foreign aid has been extensively conducted over the last three decades, but empirically the results remain inconclusive. Previous literature has relied upon linear growth model to estimate their models, methods inconsistent with the existence of poverty traps. These approaches have found that the effect of foreign is either negative, to positive, or even conditional on the policy environment in the country. More recent theoretical literature has started to point towards a nonlinear effect of foreign aid on the level of income. This nonlinear effect is consistent with a poverty trap model. To provide empirical support for this theory this paper relaxes the assumption of linearity in the model to determine if the efficacy of foreign aid is nonlinear. To accomplish this the relationship between foreign aid and the level of income is examined using a cross sectional data set of 72 countries that received Official Development Aid between 1985 and 2014 using a multivariate adaptive regressive splines (MARS) estimation. The MARS model is a nonlinear approach that systematically identifies both threshold levels and interaction terms between independent variables. Most importantly, the MARS model will detect if foreign aid has a statistically significant threshold effect. This finding would be consistent with the poverty trap hypothesis and also explain why there has been a lack of consensus so far. The results suggest that by using a nonlinear estimation we significantly improve, 18 to 44 percent reduction in the residual sum of squares, the fit of our growth model compared to an ordinary least squares estimation, as well as also detect a threshold in the effect of foreign aid that is consistent with a poverty trap hypothesis. These results are consistent when we analyze foreign aid as either a percent of gross national income—threshold at 4.6 percent—or per capita—threshold at $24.97. Below these thresholds the effect of foreign aid is either negative, or statistically zero, but when foreign aid is sufficiently large the effect is large and positive. We also detect significant interactions between foreign aid and both human capital and population growth. The policy implication being that if a country is going to experience a positive impact on their level of income the amount of foreign aid needs to be sufficiently large enough. Furthermore, the interactions suggest that some degree of selectivity should take place on which countries are best equipped to use aid.