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The Golgi apparatus modifies, sorts and packages proteins to be sent to their final destinations, whether that's within or outside of the cell. It's a core function, but little studied in the setting of cancer immunology, especially when compared to other organelles like the mitochondria or endoplasmic reticulum. "So we were interested in looking a little bit more at the Golgi apparatus. It's obviously an important organelle. How is it being changed or what is its role in T-cells in terms of fighting cancer?" said Nathaniel Oberholtzer, an M.D./Ph.D. student who worked in the lab of Shikhar Mehrotra, Ph.D., co-leader of the Cancer Biology & Immunology Research Program at MUSC Hollings Cancer Center and scientific director of the Center for Cellular Therapy in the MUSC College of Medicine. As it turns out, the healthy function of the Golgi apparatus has a lot to do with how well T-cells function in killing cancer cells. Understanding how a signaling axis mitigates Golgi stress, enabling it to perform properly, points to a possible new therapeutic target for researchers to pursue to strengthen T-cells. Not only that, but Oberholtzer's research shows how the Golgi could be used as a biomarker to select the strongest T-cells for immunotherapy. Oberholtzer, as first author, and Mehrotra, as senior author, along with a team of Hollings scientists published the research this month in Science Advances . T-cells, part of the immune system, can kill cancer cells. CAR-T cells are T-cells that have been modified in the lab to home in on proteins on the surface of an individual's cancer cells . CAR-T cells are custom-made for each patient. Both T-cells and CAR-T cells can become "exhausted" in the hostile tumor microenvironment. Mehrotra's lab looks at ways to boost these cells so that they can fight cancer for a longer time. "The whole tumor microenvironment is conducive for the tumor itself, but not for the other cells which are trying to get in there," Mehrotra said. Just like people, cells are constantly subjected to stress—stress from biochemical reactions that have become unbalanced and mechanical stress from moving. Transient stress can be good. Stressing your muscles through exercise strengthens them, and transient stress on cells can prompt them to a response that ultimately strengthens them. "But if this stress stays there, which it does in the tumor microenvironment, the cells are just in continuous stress, and that will then lead to a very different phenotype and death," Mehrotra said. However, the researchers found that treating the Golgi apparatus with hydrogen sulfide created T-cells that could take more stress. "Hydrogen sulfide is a gaseous signaling molecule present in pretty much all mammalian cell types. Typically, it's a byproduct of different cellular processes, but it's actually been shown to have really important signaling roles as well," Oberholtzer said. "It can modify proteins through a process called sulfhydration, where it modifies cysteine residues and can change their activity." In this project, Oberholtzer found that this sulfhydration process, in modifying a protein called Prdx4 within the Golgi apparatus, confers protection in an oxidative setting. "When you have the stressors that the tumor microenvironment puts on T-cells, you get a disruption, or fragmentation, of the Golgi apparatus where it essentially isn't able to do its job. Hydrogen sulfide protects against that disruption," Oberholtzer said. Looking into this protective effect then led the researchers to look more closely at the Golgi apparatus by itself. "Essentially, if you just use the Golgi apparatus as a simple marker, if T-cells have a lot of Golgi versus less, the ones that have more Golgi are much more robust at killing tumor cells and controlling tumors," Oberholtzer explained. Using cell sorting technology at the Flow Cytometry & Cell Sorting Shared Resource at Hollings, the researchers sorted T-cells according to the amount of Golgi they contained. The top 30% were labeled Golgi-hi and the bottom 30% were labeled Golgi-lo. "Basically, all the cells which are expressing high Golgi have a very different phenotype. They are less exhausted, and they are much more potent in controlling tumors," Mehrotra said. This pre-clinical work suggests that sorting T-cells into Golgi-hi and Golgi-lo and reinfusing only the Golgi-hi cells into a patient would create a better chance of controlling the tumor . "Right now, we're working on doing some validation studies in the Center for Cellular Therapy to potentially be able to start a clinical trial to see if that has a translational ability as well," Oberholtzer said. More work is also needed to understand the role of Golgi stress when all of the organelles in a cell are under stress because of the tumor microenvironment . More information: Nathaniel Oberholtzer et al, H 2 S-Prdx4 axis mitigates Golgi stress to bolster tumor-reactive T cell immunotherapeutic response, Science Advances (2024). DOI: 10.1126/sciadv.adp1152

HOUSTON--(BUSINESS WIRE)--Dec 4, 2024-- Crescent Energy Company (NYSE: CRGY) (“we” or “our”) announced today that its indirect subsidiary Crescent Energy Finance LLC (the “Issuer”) has priced its previously announced private placement pursuant to Rule 144A and Regulation S under the Securities Act of 1933, as amended (the “Securities Act”), to eligible purchasers of $400 million aggregate principal amount of 7.625% Senior Notes due 2032 (the “Additional Notes” and, together with the Existing Notes (as defined below), the “Notes”). The size of this offering was increased from the previously announced $300 million to $400 million. The Notes mature on April 1, 2032 and pay interest at the rate of 7.625% per year, payable on April 1 and October 1 of each year, with interest payments on the Additional Notes commencing on April 1, 2025. The Additional Notes were priced at 100.250% of par, plus accrued and unpaid interest from October 1, 2024. The Issuer intends to use the net proceeds from this offering, together with the net proceeds of the previously announced underwritten public offering of our Class A Common Stock (the “Equity Offering”), to fund the cash portion of the consideration for the previously announced acquisition of Ridgemar (Eagle Ford) LLC (the “Ridgemar Acquisition”). Pending the use of proceeds described in the previous sentence, the proceeds from each of this offering and the Equity Offering will be used to temporarily reduce the borrowings outstanding under our revolving credit facility and any remaining for general corporate purposes. If the Ridgemar Acquisition is not completed, the proceeds of this offering will be used to reduce the borrowings outstanding under our revolving credit facility or for general corporate purposes. This offering is not contingent on the completion of the Ridgemar Acquisition or the Equity Offering, and neither the Ridgemar Acquisition nor the Equity Offering is conditioned on the completion of this offering. This offering is expected to close on December 11, 2024, subject to customary closing conditions. The Additional Notes are being offered as additional notes under the indenture dated as of March 26, 2024, as supplemented (the “Indenture”), pursuant to which the Issuer has previously issued $700 million aggregate principal amount of 7.625% Senior Notes due 2032 (the “Existing Notes”). The Additional Notes will have substantially identical terms, other than the issue date, the first interest payment date and the initial offering price, as the Existing Notes, and the Additional Notes and the Existing Notes will be treated as a single series of securities under the Indenture and will vote together as a single class. The Notes and the related guarantees have not been registered under the Securities Act, or any state securities laws, and, unless so registered, the Notes and the guarantees may not be offered or sold in the United States except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act and applicable state securities laws. The Issuer plans to offer and sell the Additional Notes only to persons reasonably believed to be qualified institutional buyers pursuant to Rule 144A under the Securities Act and to persons outside the United States pursuant to Regulation S under the Securities Act. This communication shall not constitute an offer to sell, or the solicitation of an offer to buy, the securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. About Crescent Energy Company Crescent Energy Company is a U.S. energy company with a portfolio of assets concentrated in Texas and the Rockies. Cautionary Statement Regarding Forward-Looking Information This communication contains forward-looking statements within the meaning of Section 27A of the Securities Act, and Section 21E of the Securities Exchange Act of 1934, as amended. These statements are based on current expectations. The words and phrases “should”, “could”, “may”, “will”, “believe”, “think”, “plan”, “intend”, “expect”, “potential”, “possible”, “anticipate”, “estimate”, “forecast”, “view”, “efforts”, “target”, “goal” and similar expressions identify forward-looking statements and express our expectations about future events. This communication includes statements regarding this private placement and the Equity Offering and the use of proceeds therefrom, respectively, and the Ridgemar Acquisition and the transactions related thereto that may contain forward-looking statements within the meaning of federal securities laws. We believe that our expectations are based on reasonable assumptions; however, no assurance can be given that such expectations will prove to be correct. A number of factors could cause actual results to differ materially from the expectations, anticipated results or other forward-looking information expressed in this communication, including weather, political, economic and market conditions, including a decline in the price and market demand for natural gas, natural gas liquids and crude oil, uncertainties inherent in estimating natural gas and oil reserves and in projecting future rates of production, our hedging strategy and results, federal and state regulations and laws, recent elections and associated political volatility, the severity and duration of public health crises, actions by the Organization of the Petroleum Exporting Countries (“OPEC”) and non-OPEC oil-producing countries, the impact of the armed conflict in Ukraine, continued hostilities in the Middle East, including the Israel-Hamas conflict and heightened tensions in Iran, Lebanon and Yemen, the impact of disruptions in the capital markets, the timing and success of business development efforts, including acquisition and disposition opportunities, our ability to integrate operations or realize any anticipated operational or corporate synergies and other benefits from the Ridgemar Acquisition and the acquisition of SilverBow Resources, Inc., our reliance on our external manager, sustained cost inflation, elevated interest rates and central bank policy changes associated therewith and other uncertainties. All statements, other than statements of historical facts, included in this communication that address activities, events or developments that we expect, believe or anticipate will or may occur in the future are forward-looking statements. Such statements are subject to a number of assumptions, risks and uncertainties, many of which are beyond our control. Consequently, actual future results could differ materially from our expectations due to a number of factors, including, but not limited to, those items identified as such in the most recent Annual Report on Form 10-K and any subsequently filed Quarterly Reports on Form 10-Q or Current Reports on Form 8-K and the risk factors described thereunder, filed by Crescent Energy Company with the U.S. Securities and Exchange Commission. Many of such risks, uncertainties and assumptions are beyond our ability to control or predict. Because of these risks, uncertainties and assumptions, you should not place undue reliance on these forward-looking statements. We do not give any assurance (1) that we will achieve our expectations or (2) concerning any result or the timing thereof. All subsequent written and oral forward-looking statements concerning this offering and the Equity Offering and the use of proceeds therefrom, respectively, and the Ridgemar Acquisition and the transaction related thereto, Crescent Energy Company and the Issuer or other matters and attributable thereto or to any person acting on their behalf are expressly qualified in their entirety by the cautionary statements above. We assume no duty to update or revise these forward-looking statements based on new information, future events or otherwise. View source version on businesswire.com : https://www.businesswire.com/news/home/20241204640013/en/ IR@crescentenergyco.com KEYWORD: UNITED STATES NORTH AMERICA TEXAS INDUSTRY KEYWORD: OIL/GAS ENERGY SOURCE: Crescent Energy Copyright Business Wire 2024. PUB: 12/04/2024 05:15 PM/DISC: 12/04/2024 05:17 PM http://www.businesswire.com/news/home/20241204640013/en

Amit Shah pushes for use of tech to implement new criminal lawsThe TOI Entertainment Desk is a dynamic and dedicated team of journalists, working tirelessly to bring the pulse of the entertainment world straight to the readers of The Times of India. No red carpet goes unrolled, no stage goes dark - our team spans the globe, bringing you the latest scoops and insider insights from Bollywood to Hollywood, and every entertainment hotspot in between. We don't just report; we tell tales of stardom and stories untold. Whether it's the rise of a new sensation or the seasoned journey of an industry veteran, the TOI Entertainment Desk is your front-row seat to the fascinating narratives that shape the entertainment landscape. Beyond the breaking news, we present a celebration of culture. We explore the intersections of entertainment with society, politics, and everyday life. Read More From Deepika Padukone to Kareena Kapoor: Christmas-worthy red outfits worn by Bollywood divas Ranthambore's 10 safari zones: A guide to guaranteed tiger sightings Karisma Kapoor's saree fusion redefines the ultimate fashion statement 9 reasons to include moringa leaves in your diet on a daily basis Janhvi Kapoor gears up for a glamorous Christmas celebration 10 signs your employees are losing interest in their jobs Baby names based on adorable names of Jesus Christ ​10 classics that resonate the true spirit of Christmas​ Christmas 2024: How to make Coffee Walnut Cake for the special feastPlayoff game at Ohio State has sold 34% more tickets than Notre Dame game on StubHub