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Kochhar, Sonali,Excler, Jean-Louis,Bok, Karin,Gurwith, Marc,McNeil, Michael M.,Seligman, Stephen J.,Khuri-Bulos, Najwa,Klug, Bettina,Laderoute, Marian,Robertson, James S.,Singh, Vidisha,Chen, Robert T Elsevier Ltd. 2019 Vaccine Vol. No.
<P><B>Abstract</B></P> <P>Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely <I>potential or known</I> AEFI and establish the optimal risk window(s); and (3) conducting “near real-time“ prospective monitoring for <I>unknown</I> clustering’s of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators.</P>
Nocon, Justyna,Steiger, Matthias G.,Pfeffer, Martin,Sohn, Seung Bum,Kim, Tae Yong,Maurer, Michael,Rußmayer, Hannes,Pflü,gl, Stefan,Ask, Magnus,Haberhauer-Troyer, Christina,Ortmayr, Karin,Hann, Ste Academic Press 2014 Metabolic engineering Vol.24 No.-
<▼1><P>The production of recombinant proteins is frequently enhanced at the levels of transcription, codon usage, protein folding and secretion. Overproduction of heterologous proteins, however, also directly affects the primary metabolism of the producing cells. By incorporation of the production of a heterologous protein into a genome scale metabolic model of the yeast <I>Pichia pastoris</I>, the effects of overproduction were simulated and gene targets for deletion or overexpression for enhanced productivity were predicted. Overexpression targets were localized in the pentose phosphate pathway and the TCA cycle, while knockout targets were found in several branch points of glycolysis. Five out of 9 tested targets led to an enhanced production of cytosolic human superoxide dismutase (hSOD). Expression of bacterial β-glucuronidase could be enhanced as well by most of the same genetic modifications. Beneficial mutations were mainly related to reduction of the NADP/H pool and the deletion of fermentative pathways. Overexpression of the hSOD gene itself had a strong impact on intracellular fluxes, most of which changed in the same direction as predicted by the model. <I>In vivo</I> fluxes changed in the same direction as predicted to improve hSOD production. Genome scale metabolic modeling is shown to predict overexpression and deletion mutants which enhance recombinant protein production with high accuracy.</P></▼1><▼2><P><B>Highlights</B></P><P>•<P>Recombinant protein production in <I>P. pastoris</I> affects the central metabolism.</P>•<P>A genome scale metabolic model can predict these metabolic flux changes.</P>•<P>Mutations in central metabolic genes enhanced recombinant protein yield up to 40%.</P>•<P>These beneficial mutations were predicted by the metabolic model with high accuracy.</P></P></▼2>
Kang, Junghee,Jiang, Mei Hua,Min, Hyun Jung,Jo, Eun‐,Kyeong,Lee, Soojin,Karin, Michael,Yune, Tae Young,Lee, Sung Joong WILEY‐VCH Verlag 2011 European journal of immunology Vol.41 No.5
<P><B>Abstract</B></P><P>Traumatic spinal cord injury (SCI) is followed by massive infiltration and activation of myeloid cells such as neutrophils and macrophages, but the functions of these cells are controversial. In this study, our objective was to elucidate the in vivo role of a signaling pathway involved in activation of these innate immune cells in SCI using myeloid cell‐specific IκB kinase (IKK)‐β conditional knockout (<TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-1.gif' alt ='equation image'/> ) mice. In these mice, the <I>ikk</I>β gene has been specifically deleted from myeloid cells, compromising their in vivo IKK/NF‐κB‐dependent activation. We found that <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-2.gif' alt ='equation image'/> mice had significantly reduced neutrophil and macrophage infiltrations after SCI compared to <I>ikk</I>β<SUP>+/+</SUP> controls. SCI‐induced proinflammatory gene expression was also reduced in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-3.gif' alt ='equation image'/> mice. Reduced neuroinflammation in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-4.gif' alt ='equation image'/> mice was accompanied by attenuated neuronal loss and behavioral deficits in motor activity. In addition, the SCI‐induced expression of CXC ligand 1 was reduced in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-5.gif' alt ='equation image'/> mice, which may be responsible for the reduced neutrophil infiltration in these mice. Our data demonstrate that IKK‐β‐dependent myeloid cell activation potentiates neuroinflammation and neuronal damage after SCI.</P>
Park, Eek Joong,Lee, Jun Hee,Yu, Guann-Yi,He, Guobin,Ali, Syed Raza,Holzer, Ryan G.,Ö,sterreicher, Christoph H.,Takahashi, Hiroyuki,Karin, Michael Elsevier 2010 Cell Vol.140 No.2
<P><B>Summary</B></P><P>Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.</P> <P><B>Graphical Abstract</B></P><P><ce:figure></ce:figure></P><P><B>Highlights</B></P><P>► Obesity promotes hepatocellular carcinoma (HCC) in mice via TNF and IL-6 cytokines ► TNF and IL-6 promote liver fat accumulation and fat-induced liver inflammation ► Loss of TNF receptor 1 prevents fat-induced liver injury and HCC development ► Ablation of the IL-6 gene also prevents obesity-promoted HCC development</P>
NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice.
Kim, Sunshin,Millet, Isabelle,Kim, Hun Sik,Kim, Ja Young,Han, Myoung Sook,Lee, Moon-Kyu,Kim, Kwang-Won,Sherwin, Robert S,Karin, Michael,Lee, Myung-Shik National Academy of Sciences 2007 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.104 No.6
<P>Whereas NF-kappaB has potent antiapoptotic function in most cell types, it was reported that in pancreatic beta cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of beta cell NF-kappaB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IkappaBalpha in pancreatic beta cells (RIP-mIkappaBalpha mice). beta cells of these mice were more susceptible to killing by TNF-alpha plus IFN-gamma but more resistant to IL-1beta plus IFN-gamma than normal beta cells. Similar results were obtained with beta cells lacking IkappaB kinase beta, a protein kinase required for NF-kappaB activation. Inhibition of beta cell NF-kappaB accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4(+) T cells was accelerated in RIP-mIkappaBalpha/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-kappaB is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-kappaB in IL-1beta-stimulated beta cells.</P>