bPembrolizumab, an immunotherapy medication/b, significantly enhanced disease-free survival when added to the standard of care for patients with advanced soft tissue sarcoma of the limb.

Discover how pembrolizumab, an immunotherapy drug, enhances disease-free survival in advanced soft tissue sarcoma, offering a promising treatment alternative.

Awarded to the finance team that has displayed exceptional financial leadership by, for example, improving the charity's financial performance or by helping it to overcome significant challenges

Global flooring leader Tarkett secured six prestigious MarCom Awards, including three Platinum awards for their 2023 Design Days campaigns and website redesign, plus three Gold awards for their "Made Right Means Johnsonite" campaign.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma  Nature.com

Looking for a Marcom Manager for a full time position in the center

• Assisting in creation of marketing and marcom materials
• Working with graphical designers on companies catalogue, brochures and collateral
• Working with the web master on website updating
• Preparing and sending newsletters
• Preparing and executing company's exhibitions

Requirements:

• Proven experience in writing marketing material
• High level of familiarity with social media
• Proven experience in setting up exhibitions
• Excellent verbal and written abilities

Please send resumes to justine (at) otclih (dot) com

Organic anion transporting polypeptides (OATP, gene symbol SLCO) are well-recognized key determinants for the absorption, distribution, and excretion of a wide spectrum of endogenous and exogenous compounds including many antineoplastic agents. It was therefore proposed as a potential drug target for cancer therapy. In our previous study, it was found that low-dose X-ray and carbon ion irradiation both upregulated the expression of OATP family member OATP1A2 and in turn, led to a more dramatic killing effect when cancer cells were cotreated with antitumor drugs such as methotrexate. In the present study, the underlying mechanism of the phenomenon was explored in breast cancer cell line MCF-7. It was found that the nonreceptor tyrosine kinase v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES-1) was temporally coordinated with the change of OATP1A2 after irradiation. The overexpression of YES-1 significantly increased OATP1A2 both at the mRNA and protein level. The signal transducer and activator of transcription 3 (STAT3) pathway is likely the downstream target of YES-1 because phosphorylation and nuclear accumulation of STAT3 were both enhanced after overexpressing YES-1 in MCF-7 cells. Further investigation revealed that there are two possible binding sites of STAT3 localized at the upstream sequence of SLCO1A2, the encoding gene of OATP1A2. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis suggested that these two sites bound to STAT3 specifically and the overexpression of YES-1 significantly increased the association of the transcription factor with the putative binding sites. Finally, inhibition or knockdown of YES-1 attenuated the induction effect of radiation on the expression of OATP1A2.

SIGNIFICANCE STATEMENT

The present study found that the effect of X-rays on v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES-1) and organic anion transporting polypeptides (OATP)1A2 was temporally coordinated. YES-1 phosphorylates and increases the nuclear accumulation of signal transducer and activator of transcription 3, which in turn binds to the upstream regulatory sequences of SLCO1A2, the coding gene for OATP1A2. Hence, inhibitors of YES-1 may suppress the radiation induction effect on OATP1A2.

Hem Sapkota, Jonathan D. Wren, and Gary J. Gorbsky

Centrosomes focus microtubules to promote mitotic spindle bipolarity, a critical requirement for balanced chromosome segregation. Comprehensive understanding of centrosome function and regulation requires a complete inventory of components. While many centrosome components have been identified, others may yet remain undiscovered. We have used a bioinformatics approach, based on "guilt by association" expression to identify novel mitotic components among the large group of predicted human proteins that have yet to be functionally characterized. Here we identify Chondrosarcoma-Associated Gene 1 (CSAG1) in maintaining centrosome integrity during mitosis. Depletion of CSAG1 disrupts centrosomes and leads to multipolar spindles more effectively in cells with compromised p53 function. Thus, CSAG1 may reflect a class of "mitotic addiction" genes whose expression is more essential in transformed cells.

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC₅₀ and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient for primary effusion lymphoma (PEL) development. Alterations in cellular signaling pathways are also a characteristic of PEL. Other B cell lymphomas have acquired an oncogenic mutation in the myeloid differentiation primary response 88 (MYD88) gene. The MYD88 L265P mutant results in the activation of interleukin-1 receptor associated kinase (IRAK). To probe IRAK/MYD88 signaling in PEL, we employed CRISPR/Cas9 technology to generate stable deletion clones in BCBL-1Cas9 and BC-1Cas9 cells. To look for off-target effects, we determined the complete exome of the BCBL-1Cas9 and BC-1Cas9 cells. Deletion of either MYD88, IRAK4, or IRAK1 abolished interleukin-1 beta (IL-1β) signaling; however, we were able to grow stable subclones from each population. Transcriptome sequencing (RNA-seq) analysis of IRAK4 knockout cell lines (IRAK4 KOs) showed that the IRAK pathway induced cellular signals constitutively, independent of IL-1β stimulation, which was abrogated by deletion of IRAK4. Transient complementation with IRAK1 increased NF-B activity in MYD88 KO, IRAK1 KO, and IRAK4 KO cells even in the absence of IL-1β. IL-10, a hallmark of PEL, was dependent on the IRAK pathway, as IRAK4 KOs showed reduced IL-10 levels. We surmise that, unlike B cell receptor (BCR) signaling, MYD88/IRAK signaling is constitutively active in PEL, but that under cell culture conditions, PEL rapidly became independent of this pathway.

IMPORTANCE One hundred percent of primary effusion lymphoma (PEL) cases are associated with Kaposi sarcoma-associated herpesvirus (KSHV). PEL cell lines, such as BCBL-1, are the workhorse for understanding this human oncovirus and the host pathways that KSHV dysregulates. Understanding their function is important for developing new therapies as well as identifying high-risk patient groups. The myeloid differentiation primary response 88 (MYD88)/interleukin-1 receptor associated kinase (IRAK) pathway, which has progrowth functions in other B cell lymphomas, has not been fully explored in PEL. By performing CRISPR/Cas9 knockout (KO) studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in interleukin-10 (IL-10) production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.

Yen-Ling Lian, Kuan-Wei Chen, Yu-Ting Chou, Ting-Ling Ke, Bi-Chang Chen, Yu-Chun Lin, and Linyi Chen

Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. Although transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common childhood soft-tissue sarcoma. The largest subtype of RMS is embryonal rhabdomyosarcoma (ERMS) and accounts for 53% of all RMS. ERMS typically occurs in the head and neck region, bladder, or reproductive organs and portends a promising prognosis when localized; however, when metastatic the 5-yr overall survival rate is ~43%. The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients. Here, we report genomic, phenotypic, and bioinformatic analyses for a case of a 3-yr-old male who presented with bladder ERMS. Additionally, we use an unsupervised agglomerative clustering analysis of RNA and whole-exome sequencing data across ERMS and undifferentiated pleomorphic sarcoma (UPS) tumor samples to determine several major endotypes inferring potential targeted treatments for a spectrum of pediatric ERMS patient cases.

UTStarcom Inc. (UTSI) has entered into an agreement with the Department of Justice, agreeing to pay a $1.5 million fine for violations of the Foreign Corrupt Practices Act by providing travel and other things of value to foreign officials, specifically employees at state-owned telecommunications firms in the People’s Republic of China.

Today Kevin’s game, Starcom: Nexus, releases in Early Access on Steam. It’s a thing of beauty, and also a lot of fun. If you like games that take you into outer space where you get to explore mysterious worlds, build a powerful ship, and explode bad guys, you should buy it, and play it, and let your gamer friends know about it. Yes, I’m biased, but reviewers and streamers  - who are not his spouse  - also love it :o). (FYI those last two links go to youtube streaming vids.)

***

Conversation at the dinner table:

Kevin: How was your day?

Me: Okay, I guess. I still can’t figure out how to get this girl to accidentally set her house on fire, then cause an explosion and get stuck in a window grille.

Kevin: I believe in you.

Me: Thank you. How was your day?

Kevin: Okay. When my enemy ships get within a certain distance of each other, they spontaneously explode.

Me: Oh!

Kevin: It’s not supposed to happen. It’s a bug.

Me: Oh.

Kevin: I can’t figure it out.

Me: I believe in you!

***


There are a lot of similarities between the work Kevin and I do. We both create complicated worlds with characters and plots. We’re both entertainers.

Meet your commander.

We have some processes in common: for example, we both study the books/games we love, then try to learn from them. We both think about the things we don’t like in other books/games, then try to come up with alternatives we prefer. We both know how to wear the creator hat; then switch to the reader/gamer hat, reading/playing our own project with a critical eye; then go back to the creator hat to fix what isn’t working. We’re both extremely familiar with the phenomenon wherein you change one little thing, then a ripple effect passes through the entire work, complicating/breaking things in ways you didn’t anticipate.

Meet the Ulooquo, an underwater alien race.

We can also get similarly overwhelmed by our own projects. I’ve talked a lot on the blog about how a book has many parts, and writing a book involves many jobs. Well, a game has SO many parts. It has music and art, visual effects, numerous interfaces, plot and character, mysteries and rewards. It must be able to support and absorb the choices of individual gamers, over which the creator has no control. It has SO many (literally) moving parts!



We also both work by ourselves for years on self-directed projects… then put our creations out into the world, hoping they’ll find the people who will love them.

These similarities are deep. They help us to understand each other’s frustrations and joys, and support each other meaningfully. This is awesome. However, I want to talk a little bit about the differences, which are many.

For example, in my writing career, I have an agent. She connects me to an editor who helps me craft the right words. Then, my editor works with my publisher to create a beautiful physical book, publicize and market that book, and sell that book for me.

An indie game developer, on the other hand, does everything himself, in an extremely saturated market with a lot of roadblocks. He can hire other people to help. Kevin hired a composer and an artist, to help him with his music and his characters (like the Commander and the Ulooquo above). He hired a marketing consultant to do a few things too. But he worked closely with those people, because he knew exactly what he wanted. And everything else has been the work of his own hands. He’s done SO much marketing and publicity work on his own that’s made me appreciate my own marketing and publicity departments even more than I did before. Self-promotion in a saturated market is really, really hard. It’s also stressful for a guy who happens to be humble and was raised with the good-old New England ethos of not bragging about himself :o).

Here’s another big difference: Kevin can release his game while it’s still in production, then use the feedback from early players to shape it and make it better. He can write code into the game that allows him to see how long players play; where they decide to drop out of the game; which options are being chosen more often than others. (He receives this information anonymously, in case you’re starting to worry that he can actually tell what you’re doing inside his game!) As a writer, I definitely don’t know where someone decides to abandon my book. Nor do I want to know, because once people are reading my book, it’s final! If everyone is bailing at a certain point, there’s nothing I can do about it. The words in my book are not going to change. Kevin’s game is more of a living, growing creature, even after it releases, and based on player reactions.

Another big difference is that while I am a wordsmith, Kevin is a programmer. A lot of the time, when I step into his office, he’s working with programming language on his many screens, and I don’t understand the smallest bit of it. My readers read my actual words. His gamers play a game built on a framework of programming that looks and feels very different from the actual game. He also works with a lot of complicated software (like, for 3D modeling) and does a lot of math. He uses trigonometry to [I just asked him to explain it and he said something about spaceships shooting at each other, vectors, and cosines. ???]. I can come home and tell him practically everything I struggled with at work that day. A lot of what he does is too technical for me to understand—though he is really good at creating analogies and explaining things to me when I ask (and when I'm not rushing to finish a blog post!).

Another difference is that he is a visual artist. For example, he created Entarq's Citadel below, which is one of the worlds his gamers get to explore.


Here's another.


Another difference:  I can do my work anywhere. All I need is my notebook and a pen. Kevin needs his fancy computer and his big monitors. So he works from home. Home office and self-employed means he’s working most of the time. Most mornings, he’s working by the time I get out of bed. By the time I leave for my office, he’s put hours in. I come home and he’s making me dinner; after dinner, he works for a few more hours. I go away on trips without him; he works while I’m gone! I always thought I worked really hard. I have a new standard now.

And now his work has created this beautiful, fun game that’s getting really positive attention from gamers and streamers :o). Today, you can buy it in Early Access, and become one of the players who contributes to what it will ultimately become.

And that's my little explanation of what it's like to live with an indie game developer. Check out the links if you’re interested! The trailer is below.

A new study offers insight into genetic alterations associated with osteosarcoma, the most common bone tumor of children and adolescents, and the findings have implications for genetic testing of children with osteosarcoma and their families.