Oncotarget: PD-1/PD-L1 Expression in Anal Squamous Intraepithelial Lesions (Medicine)

Oncotarget recently published “PD-1/PD-L1 expression in anal squamous intraepithelial lesions” which reported that the presence and distribution of CD8 lymphocytes and the presence of PD-1 lymphocytes and PD-L1 epithelial cells were assessed.

CD8 lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial.

PD-1 lymphocytes were observed more frequently in HSIL versus LSIL.

There was no difference between HSIL and LSIL for PD-L1 epithelial cells.

Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions.

Dr. Margot Bucau from The Hôpital Bichat-Claude Bernard said, “Anal intraepithelial neoplasia (AIN) is the precursor lesion for anal squamous cell carcinomas (ASCC).

Dr. Margot Bucau from The Hôpital Bichat-Claude Bernard said, “Anal intraepithelial neoplasia (AIN) is the precursor lesion for anal squamous cell carcinomas (ASCC).

Since 2012, the Lower Anogenital Squamous Terminology recommended denomination for HPV-associated squamous lesions of the lower anogenital tract as low-grade and high-grade squamous intraepithelial lesion.

Oncogenic HPV infection plays a crucial role in developing both cervical and anal lesions, by the integration of the viral DNA into the epithelial cells and activation of oncogenic early proteins E6 and E7. This causes downregulation of suppressing tumor genes, especially TP53 and Rb, and upregulation of p16.

In the cervix, HPV related cancer often have increased infiltration by immune cell populations, including cytotoxic CD8 T cells, that correlates with better response to chemoradiotherapy and increased survival compared to immune-deprived tumors.

Figure: Morphological and immunohistochemical (PD-1, PD-L1, and CD8) aspects in a patient with AIN1 and AIN3. HES: Hematoxylin, Eosin and Saffron stain for morphological assessment. (A) AIN1 lesion stained with HES. (B) AIN3 lesion stained with HES. (C) CD8 immunostain scored 1 for both band-like infiltrate (arrowheads) and intra-epithelial lymphocytes (arrows) in AIN1 lesion. (D) CD8 immunostain scored 3 and 1 respectively for band-like infiltrate (arrowheads) and intra-epithelial lymphocytes (arrows) in AIN3 lesion. (E) PD-1 immunostain (score 0: no infiltrate) in AIN1 lesion. (F) PD-1 immunostain (score 3: abondant lymphocytic infiltrate) in AIN3 lesion. (G) PD-L1 immunostain (no positive epithelial cells or lymphocytes) in AIN1 lesion. (H) PD-L1 immunostain (40% of PD-L1+ epithelial cells) in AIN3 lesion. The positive cells are large epithelial squamous cells and no lymphocytes are marked. ©Oncotarget

Moreover, p16 positive tumors were shown to present higher tumor-infiltrating lymphocytes density and better recurrence-free survival.

The Bucau Research Team concluded in their Oncotarget Research Paper, “our exploratory study highlights the interest of the PD-1/PD-L1 pathway in anal dysplasia and the importance to further explore the different mechanisms of immune micro environment in the progression of anal intra epithelial lesion. It suggests the potential role of therapeutic molecules targeting the immune response to slow down the tumor progression in selected patients with HSIL.

DOI – https://doi.org/10.18632/oncotarget.27756

Full text – https://www.oncotarget.com/article/27756/text/

Provided by Impact Journals LLC

Oncotarget: Targeted Lymphodepletion With a CD45-directed Antibody Radioconjugate (Medicine)

Oncotarget recently published “Targeted lymphodepletion with a CD45-directed antibody radioconjugate as a novel conditioning regimen prior to adoptive cell therapy” which reported that Chimeric antigen receptor T cell therapies, and adoptive cell therapy in general, represent one of the most promising anti-cancer strategies.

In contrast to relatively non-specific chemotherapy-derived lymphodepletion, targeted lymphodepletion with radioimmunotherapy directed to CD45 may be a safer and more effective alternative to target and deplete immune cells. Here the authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters 131Iodine and 177Lutetium, to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy.

Treatment of mice with 3.7 MBq 131I-30F11 or 1.48 MBq 177Lu-30F11 safely depleted immune cells such as spleen CD4 and CD8 T Cells, B and NK cells as well as Tregs in OT I tumor model while sparing RBC and platelets and enabled E. G7 tumor control. These results support the application of CD45-targeted RIT lymphodepletion with a non-myeloablative dose of 131I-30F11 or 177Lu-30F11 antibody prior to adoptive cell therapy.

Dr. Dale L. Ludwig from Actinium Pharmaceuticals said, “Chimeric antigen receptor (CAR) T cell therapies, and adoptive cell therapy (ACT) in general, represent one of the most promising anti-cancer strategies.

It is unclear why some patients respond to treatment with adoptive cell therapies such as CAR-T, and others do not, though the tumor immune microenvironment is a likely contributor to variable effect of cell therapy in both hematologic and solid cancers.

Other cell types that contribute to an immunosuppressive tumor microenvironment that may negatively impact CAR-T efficacy include myeloid derived suppressor cells and tumor-associated macrophages.

Figure: Comparative tumor control by 177Lu-30F11 or 131I-30F11 antibody. Following E. G7 tumor engraftment, mice either received no treatment or were conditioned with 1.48 MBq 177Lu-30F11 or 3.7 MBq 131I-30F11 on Day 0 and then received 106 OT I CD8+ CD45.2 OVA reactive T cells on day 4. (A) 177Lu-30F11 and 131I-CD45-mediated targeted conditioning prior to adoptively transferred OT I T cells enabled control of E.G7 tumor growth. (B) Tumor size for individual mice in each group is displayed. OT I T cell persistence and expansion was confirmed in mice at the time of sacrifice. (C) Survival of mice in treated and in untreated control groups. © Oncotarget

The CD45 antigen is found on all nucleated immune cells, with increased expression on mature lymphoid and myeloid lineages, leading to preferential depletion of mature immune cells compared to progenitor hematopoietic cells.

Importantly, immunomodulatory cells such as Tregs and MDSC express CD45 and are targets of lymphodepletion with a CD45-targeting antibody-radionuclide conjugate, potentially resulting in better engraftment, activation and persistence of the exogenously added CAR-T cells in patients.

Here the Oncotarget authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11, labeled with two different beta-emitters – 131I and 177Lutetium, to investigate the effect of anti-CD45 RIT lymphodepletion on immune cell types and on tumor control in a model of adoptive cell therapy.

“Here the Oncotarget authors describe the results of preclinical studies with an anti-mouse CD45 antibody 30F11”

The Ludwig Research Team concluded in their Oncotarget Research Paper, “our data supports CD45 targeted RIT lymphodepletion with a non-myeloablative dose of 131I-30F11 or 177Lu-30F11 prior to adoptive cell therapy.

DOI – https://doi.org/10.18632/oncotarget.27731

Full text – https://www.oncotarget.com/article/27731/text/

Provided by Impact Journals LLC

A Potent Weapon Against Lymphomas (Medicine)

MDC researchers have developed a new approach to CAR T-cell therapy. The team has shown in Nature Communications that the procedure is very effective, especially when it comes to fighting follicular lymphomas and chronic lymphocytic leukemia, the most common type of blood cancer in adults.

The body’s defense system generally does not recognize cancer cells as dangerous. To correct this sometimes fatal error, researchers are investigating a clever new idea, one that involves taking a handful of immune cells from cancer patients and “upgrading” them in the laboratory so that they recognize certain surface proteins in the malignant cells. The researchers then multiply the immune cells and inject them back into the patients’ blood – setting them off on a journey through the body to detect and attack all cancer cells in a targeted way.

In fact, the first treatments based on this idea have already been approved: So-called CAR T cells have been used in Europe since 2018, particularly in patients with B-cell lymphomas for whom conventional cancer therapies have not worked.

T cells are like the immune system’s police force. The abbreviation CAR stands for “chimeric antigen receptor“ – meaning that the cellular police force is equipped with a new, laboratory-designed special antenna that targets a surface protein on the cancer cells. Thanks to this antenna, a small number of T cells can round up a large number of cancer cells and destroy them. Ideally, the CAR T cells patrol the body for weeks, months or even years and thus prevent tumor relapse.

A kind of signpost for B cells

Until now, the antenna on the CAR T cells was primarily directed against the protein CD19, which B cells – a type of immune cells – carry on their surface. Yet this form of therapy is by no means effective in all patients. A team led by Dr. Uta Höpken, head of the Microenvironmental Regulation in Autoimmunity and Cancer Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now developed a new twist on this therapy that sensitizes the T cells in the laboratory to a different identifying feature: the B-cell homing protein CXCR5.

“CXCR5 was first described at the MDC more than 20 years ago, and I have been studying this protein myself for almost as long,” says Höpken. “I am therefore very pleased that we have now succeeded in using CXCR5 to effectively combat non-Hodgkin’s lymphomas, such as follicular and mantle cell lymphoma as well as chronic lymphocytic leukemias, in the laboratory.” This protein is a receptor that helps mature B cells move from the bone marrow – where they are produced – to immune system organs such as the lymph nodes and spleen. “Without the receptor, the B cells would not find their way to their target site, the B-cell follicles of these lymphoid organs,” Höpken explains.

Anti-CXCR5 CAR-T cells (green) attack lymphoma cells (magenta) within the stroma cell network of the B cell follicle (light blue). © AG Höpken / Rehm, MDC

A well-suited target

“All mature B cells, including malignant ones, carry this receptor on their surface. So it seemed to us to be well suited to detect B-cell tumors – thereby enabling CAR-T cells directed against CXCR5 to attack the cancer,” says Janina Pfeilschifter, a PhD student in Höpken’s team. She and Dr. Mario Bunse from the same research group are the lead authors of the paper, which appeared in the journal Nature Communications. “In our study, we have shown through experiments with human cancer cells and two mouse models that this immunotherapy is most likely safe and very effective,” says Pfeilschifter.

The new approach may be particularly well suited for patients with a follicular lymphoma or chronic lymphocytic leukemia (CLL). “Both types of cancer involve not only B cells but also follicular T helper cells, which also carry CXCR5 on their surface,” Bunse explains. The special antenna for the identifying feature, the CXCR5-CAR, was generated by Dr. Julia Bluhm during her time as a PhD student in the MDC’s Translational Tumorimmunology Lab, which is headed by physician Dr. Armin Rehm. He and Höpken are the corresponding authors of the study.

First successes in the petri dish

Pfeilschifter and Bunse first showed that various human cells, for example, from blood vessels, the gut and the brain, do not carry the CXCR5 receptor on their surface and are therefore not attacked in the petri dish by T cells equipped with CXCR5-CAR. “This is important to prevent unexpected organ damage from occurring during therapy,” Pfeilschifter explains. In contrast, experiments with human tumor cell lines showed that malignant B cells from very different forms of B-non-Hodgkin’s lymphoma all display the receptor.

Professor Jörg Westermann, from the Division of Hematology, Oncology and Tumor Immunology in the Medical Department of Charité – Universitätsmedizin Berlin at the Campus Virchow Clinic, also provided the team with tumor cells from patients with CLL or B-non-Hodgkin’s lymphomas. “There, too, we were able to detect CXCR5 on all B-lymphoma cells and follicular T helper cells,” Pfeilschifter says. When she and Bunse placed the tumor cells in the petri dish together with the CXCR5-targeted CAR T cells, almost all of the malignant B and T helper cells disappeared from the tissue sample after 48 hours.

Mice with leukemia were cured

The researchers also tested the new procedure on two mouse models. “The CAR T cells are infused into the blood of cancer patients,” Höpken says. “So animal research is needed to show that the cells home to the niches where the cancer resides, multiply there and then do their job effectively.”

“No laboratory can tackle such a study on its own. It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.”, said Uta Höpken, Head of the lab “Microenvironmental Regulation in Autoimmunity and Cancer”.

One model consisted of animals with a severely suppressed immune system, which could therefore be treated with human CAR T cells without causing rejection reactions. “We also developed a pure mouse model for CLL specifically for the current study,” Bunse reports. “We administered mouse CAR T cells against CXCR5 to these animals by infusion and were able to eliminate mature B cells and T helper cells, including malignant ones, from the B-cell follicles of the lymphoid organs.”

The researchers discovered no serious side effects in the mice. “We know from experience with cancer patients that CAR T-cell therapy increases the risk of infection for a few months,” Rehm says. But in practice this side effect is almost always easily managed.

A clinical trial is in the works

”No laboratory can tackle such a study on its own,” Höpken emphasizes. “It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.” For her, the study is the first step toward creating a “living drug” – similar to other cellular immunotherapies being developed at MDC. “We are already cooperating with two cancer specialists at Charité and are currently working with them to prepare a phase 1/2 clinical trial,” adds Höpken’s colleague Rehm. Both hope that the first patients will begin to benefit from their new CAR-T cell therapy in the near future.

The German José Carreras Leukemia Foundation has funded the research with around 240,000 euros over a period of three years. The non-profit organization supports forward-looking research projects and infrastructure projects that investigate the causes of leukemia and improve treatment, as well as social projects.

Reference: Bunse, M., Pfeilschifter, J., Bluhm, J. et al. CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells. Nat Commun 12, 240 (2021). https://www.nature.com/articles/s41467-020-20488-3 https://doi.org/10.1038/s41467-020-20488-3

Provided by Max Delbruck Center for Molecular Medicine

A Safer, Less Expensive and Fast Charging Aqueous Battery (Engineering)

New Anode for Aqueous Batteries Allows Use of Cheap, Plentiful Seawater as an Electrolyte.

Lithium-ion batteries are critical for modern life, from powering our laptops and cell phones to those new holiday toys. But there is a safety risk – the batteries can catch fire.

Zinc-based aqueous batteries avoid the fire hazard by using a water-based electrolyte instead of the conventional chemical solvent. However, uncontrolled dendrite growth limits their ability to provide the high performance and long life needed for practical applications.

An electric fan (top left) is powered by the proposed zinc battery; typical charge/discharge profiles of ZIBs at 0.5C (top right); in-situ microscope setup to image the zinc deposition dynamics (bottom left); and the morphology change caused by the zinc deposition (bottom right). © University of Houston

Now researchers have reported in Nature Communications that a new 3D zinc-manganese nano-alloy anode has overcome the limitations, resulting in a stable, high-performance, dendrite-free aqueous battery using seawater as the electrolyte.

Xiaonan Shan, co-corresponding author for the work and an assistant professor of electrical and computer engineering at the University of Houston, said the discovery offers promise for energy storage and other applications, including electric vehicles.

“It provides a low-cost, high energy density, stable battery,” he said. “It should be of use for reliable, rechargeable batteries.”

Shan and UH PhD student Guangxia Feng also developed an in situ optical visualization technique, allowing them to directly observe the reaction dynamics on the anode in real time. “This platform provides us with the capability to directly image the electrode reaction dynamics in situ,” Shan said. “This important information provides direct evidence and visualization of the reaction kinetics and helps us to understand phenomena that could not be easily accessed previously.”

Testing determined that the novel 3D zinc-manganese nano alloy anode remained stable without degrading throughout 1,000 hours of charge/discharge cycling under high current density (80 mA/cm²).

The anode is the electrode which releases current from a battery, while electrolytes are the medium through which the ionic charge flows between the cathode and anode. Using seawater as the electrolyte rather than highly purified water offers another avenue for lowering battery cost.

Xiaonan Shan, assistant professor of electrical and computer engineering, said the discovery offers promise for energy storage and other applications, including electric vehicles. © University of Houston

Traditional anode materials used in aqueous batteries have been prone to dendrites, tiny growths that can cause the battery to lose power. Shan and his colleagues proposed and demonstrated a strategy to efficiently minimize and suppress dendrite formation in aqueous systems by controlling surface reaction thermodynamics with a zinc alloy and reaction kinetics by a three-dimensional structure.

Shan said researchers at UH and University of Central Florida are currently investigating other metal alloys, in addition to the zinc-manganese alloy.

In addition to Shan and Feng, researchers on the project include Huajun Tian, Zhao Li, David Fox, Lei Zhai, Akihiro Kushima and co-corresponding author Yang Yang, all with the University of Central Florida; Zhenzhong Yang and Yingge Du, both with Pacific Northwest National Laboratory; Maoyu Wang and co-corresponding author Zhenxing Feng, both with Oregon State University; and Hua Zhou with Argonne National Laboratory.

Reference: Tian, H., Li, Z., Feng, G. et al. Stable, high-performance, dendrite-free, seawater-based aqueous batteries. Nat Commun 12, 237 (2021). https://www.nature.com/articles/s41467-020-20334-6 https://doi.org/10.1038/s41467-020-20334-6

Provided by University of Houston

To Understand Periodontal Disease, Researchers Examine the Surprising Behavior of T Cells (Medicine)

In diseases characterized by bone loss—such as periodontitis, rheumatoid arthritis, and osteoporosis—there is a lot that scientists still don’t understand. What is the role of the immune response in the process? What happens to the regulatory mechanisms that protect bone?

In a paper published recently in Scientific Reports, researchers from the Forsyth Institute and the Universidad de Chile describe a mechanism that unlocks a piece of the puzzle. Looking at periodontal disease in a mouse model, scientists found that a specific type of T cell, known as regulatory T cells, start behaving in unexpected ways. These cells lose their ability to regulate bone loss and instead begin promoting inflammation.

“That is important because in many therapies analyzed in in-vivo models, researchers usually check if the number of regulatory T cells has increased. But they should check if these cells are indeed functioning,” says Dr. Carla Alvarez, a postdoctoral researcher at Forsyth and lead author of the paper.

Regulatory T cells control the body’s immune response. In periodontal disease, bone loss occurs because the body’s immune system responds disproportionately to the microbial threat, causing inflammation and destroying healthy tissue. Normally, regulatory T cells help suppress that destruction, but they appear to lose their suppressive abilities during periodontal disease.

This process is analyzed in the field of osteoimmunology, which explores the complex interactions between the immune system and bone metabolism.

“This is an interesting mechanism highlighting how bone loss is taking place in periodontal disease,” says Dr. Alpdogan Kantarci, Senior Member of Staff at Forsyth and co-author of the paper together with Dr. Rolando Vernal, Professor from the School of Dentistry at Universidad de Chile.

In the case of periodontal disease, a potential therapy targeting regulatory T cells could restore the T cells’ normal functioning, not just increase their numbers.

“Unfortunately, this is not a linear process—that’s the complicated part,” Kantarci says.

Periodontal disease is initiated by microbes in the mouth, making it all the more complex.

“The relationship between immune response and bone is not so straightforward,” says Alvarez. “There are multiple components. You have to imagine a complex network of signaling and cells that participate.” This cellular and microbial complexity is what makes the disease so difficult to study in humans. However, examining this mechanism in humans is the next step of the research, Alvarez says. The research team is planning a collaborative study to look at healthy and diseased patients, intending to observe similar mechanisms to what was seen in the animal model.

Reference: Alvarez, C., Suliman, S., Almarhoumi, R. et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep 10, 19018 (2020). https://www.nature.com/articles/s41598-020-76038-w https://doi.org/10.1038/s41598-020-76038-w

Provided by Forsyth

Study: New Insights on the Role of the MLL4 Gene in Kabuki Syndrome (Neuroscience)

Research suggests that MLL4 controls production of neurons vital to growth.

But a study published on Jan. 11 in Nature Communications illuminates new details regarding how this occurs.

The research suggests that MLL4 controls the production of neurons that secrete growth hormone-releasing hormone (GHRH) in a part of the brain called the hypothalamus. Mice without working copies of the MLL4 gene in this area had stunted growth and markedly fewer GHRH neurons. Mice with only one functioning copy of the gene had similar problems.

These are important insights, as GHRH stimulates production of the growth hormone in the pituitary gland in both mice and people. While the effects of Kabuki syndrome vary, delayed growth and short stature are common among patients.

“Given our findings, inactivation of MLL4 is presumed to lead to a loss of GHRH-neurons, resulting in lack of typical growth in Kabuki patients,” says Jae Lee, PhD, professor of biological sciences in the University at Buffalo College of Arts and Sciences. “We also researched the epigenetic activity of MLL4, and our studies suggest that MLL4 could be a great epigenetic target molecule to treat various symptoms of Kabuki syndrome.”

“This is the first study that demonstrates roles of MLL4 in fate determination of neuronal cell types during development, a significant advance in our efforts to understand how cell fates are determined epigenetically, an important question remaining to be answered in modern neurobiology,” says Seunghee Lee, associate professor of pharmacy at Seoul National University.

Jae Lee and Seunghee Lee are the study’s senior authors. The first author is Christian Huisman, PhD, a postdoctoral scholar at Oregon Health & Science University.

A detailed look at the work of MLL4

For patients, parents and caregivers, new knowledge about the biology of rare diseases provides hope, laying a foundation for the development of treatments, says Jae Lee, who is the parent of a child with a different rare genetic disorder (FOXG1 syndrome).

Microscope images: Dark granular areas show expression of mRNA for growth hormone-releasing hormone (GHRH) in the hypothalamus of a young mouse with functioning copies of the MLL4 gene (top), and of a littermate with the MLL4 gene deleted (bottom). A new study found that MLL4 controls production of neurons that secrete GHRH, with production of GHRH markedly reduced in both postnatal and embryonic mice that have the MLL4 gene deleted. Credit: Christian Huisman, originally published in Nature Communications.

Though mutations in different genes can lead to Kabuki syndrome, mutations in MLL4 are one of the most common causes of the disorder.

As part of the new study, the team used cutting-edge techniques to investigate the molecular mechanisms by which MLL4 controls the creation of GHRH-neurons in embryonic development in mice. The research shows that MLL4 helps to activate various genes involved in producing GHRH neurons, and finds that a transcription factor called NRF1 is a key partner in this process.

Moreover, the scientists showed that small chemicals that mimic the epigenetic actions of MLL4 can help to restore production of GHRH neurons.

While growth hormone therapies already exist, Jae Lee says the new research creates opportunities for exploring treatment pathways for other Kabuki syndrome symptoms.

“Kabuki syndrome has many other symptoms that are not treatable, and targeting the epigenetic activities of MLL4 could be a feasible strategy for treating other symptoms,” Jae Lee says. “The principle we found — dealing with the roles of the epigenetic activity of MLL4 in cell-type specification — may apply to various symptoms.”

In addition to Jae Lee, Seunghee Lee and Huisman, authors of the study include Young A Kim at Seoul University; Shin Jeon, Bongjin Shin, Younjung Park, Medha K. C. and Soo-Kyung Lee at UB; Jeonghoon Choi at Oregon Health & Science University; and Su Jeong Lim, Sung Min Youn and Sangsoo Kim at Soongsil University.

The research was funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases, both part of the U.S. National Institutes of Health; the Soongsil University Research Fund; the National Research Foundation of Korea; and the Korea Health Industry Development Institute.

Reference: Huisman, C., Kim, Y.A., Jeon, S. et al. The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus. Nat Commun 12, 256 (2021). https://www.nature.com/articles/s41467-020-20511-7 https://doi.org/10.1038/s41467-020-20511-7

Provided by University of Buffalo

Measurements of Pulsar Acceleration Reveal Milky Way’s Dark Side (Planetary Science)

It is well known that the expansion of the universe is accelerating due to a mysterious dark energy. Within galaxies, stars also experience an acceleration, though this is due to some combination of dark matter and the stellar density. In a new study to be published in Astrophysical Journal Letters researchers have now obtained the first direct measurement of the average acceleration taking place within our home galaxy, the Milky Way. Led by Sukanya Chakrabarti at the Institute for Advanced Study with collaborators from Rochester Institute of Technology, University of Rochester, and University of Wisconsin-Milwaukee, the team used pulsar data to clock the radial and vertical accelerations of stars within and outside of the galactic plane. Based on these new high-precision measurements and the known amount of visible matter in the galaxy, researchers were then able to calculate the Milky Way’s dark matter density without making the usual assumption that the galaxy is in a steady-state.

The ripples in the Milky Way disk are shown, along with the tidal debris from the Sagittarius dwarf galaxy. The pulsars analyzed by Chakrabarti et al 2021 to calculate Galactic accelerations are shown in the inset. © IAS; Dana Berry

“Our analysis not only gives us the first measurement of the tiny accelerations experienced by stars in the galaxy, but also opens up the possibility of extending this work to understand the nature of dark matter, and ultimately dark energy on larger scales,” stated Chakrabarti, the paper’s lead author and a current Member and IBM Einstein Fellow at the Institute for Advanced Study.

Stars hurtle through the galaxy at hundreds of kilometers per second, yet this study indicates that the change in their velocities is occurring at a literal snail’s pace–a few centimeters per second, which is about the same speed as a crawling baby. To detect this subtle motion the research team relied on the ultraprecise time-keeping ability of pulsars that are widely distributed throughout the galactic plane and halo–a diffuse spherical region that surrounds the galaxy.

“By exploiting the unique properties of pulsars, we were able to measure very small accelerations in the Galaxy. Our work opens a new window in galactic dynamics,” said co-author Philip Chang of the University of Wisconsin-Milwaukee.

Extending outwards approximately 300,000 light years from the galactic center, the halo may provide important hints to understanding dark matter, which accounts for about 90 percent of the galaxy’s mass and is highly concentrated above and below the star-dense galactic plane. Stellar motion in this particular region–a primary focus of this study–can be influenced by dark matter. Utilizing the local density measurements obtained through this study, researchers will now have a better idea of how and where to look for dark matter.

While previous studies assumed a state of galactic equilibrium to calculate average mass density, this research is based on the natural, non-equilibrium state of the galaxy. One might analogize this to the difference between the surface of a pond before and after a stone is tossed in. By accounting for the “ripples” the team was able to obtain a more accurate picture of reality. Though in this case, rather than stones, the Milky Way is influenced by a turbulent history of galactic mergers and continues to be perturbed by external dwarf galaxies like the Small and Large Magellanic Clouds. As a result, stars do not have flat orbits and tend to follow a path similar to that of a warped vinyl record, crossing above and below the galactic plane. One of the key factors that enabled this direct observational approach was the use of pulsar data compiled from international collaborations, including NANOGrav (North American Nanohertz Observatory for Gravitational Waves) that has obtained data from the Green Bank and Arecibo telescopes.

This landmark paper expands upon the work of Jan H. Oort (1932); John Bahcall (1984); Kuijken & Gilmore (1989); Holmberg & Flynn (2000); Jo Bovy & Scott Tremaine (2012) to calculate the average mass density in the galactic plane (Oort limit) and local dark matter density. IAS scholars including Oort, Bahcall, Bovy, Tremaine, and Chakrabarti have played an important role in advancing this area of research.

“For centuries astronomers have measured the positions and speeds of stars, but these provide only a snapshot of the complex dynamical behavior of the Milky Way galaxy,” stated Scott Tremaine, Professor Emeritus at the Institute for Advanced Study. “The accelerations measured by Chakrabarti and her collaborators are directly caused by the gravitational forces from the matter in the galaxy, both visible and dark, and thereby provide a new and promising window on the distribution and the composition of the matter in the galaxy and the universe.”

This particular paper will enable a wide variety of future studies. Accurate measurements of accelerations will also soon be possible using the complementary radial velocity method that Chakrabarti developed earlier this year, which measures the change in the velocity of stars with high precision. This work will also enable more detailed simulations of the Milky Way, improve constraints on general relativity, and provide clues in the search for dark matter. Extensions of this method may ultimately allow us to directly measure the cosmic acceleration as well.

While a direct picture of our home galaxy–similar to the ones of Earth taken by the Apollo astronauts–is not yet possible, this study has provided essential new details to help envision the dynamic organization of the galaxy from within.

Reference: https://www.ias.edu/news/2021/galactic-acceleration

Provided by Institute for Advanced Study

One in Five Brain Cancers Fueled by Overactive Mitochondria (Medicine)

A new study has found that up to 20% of glioblastomas–an aggressive brain cancer–are fueled by overactive mitochondria and may be treatable with drugs currently in clinical trials.

Mitochondria are responsible for creating the energy that fuels all cells. Though they are usually less efficient at producing energy in cancer, tumor cells in this newly identified type of glioblastoma rely on the extra energy provided by overactive mitochondria to survive.

The study, by cancer scientists at Columbia University’s Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center, was published online Jan. 11 in Nature Cancer.

The study also found that drugs that inhibit mitochondria–including a currently available drug and an experimental compound that are being tested in clinical trials–had a powerful anti-tumor effect on human brain cancer cells with overactive mitochondria. (Follow-up, unpublished work found that the same drugs are also active against mitochondrial tumors in glioblastomas growing in mice).

Such drugs are being tested in patients who have a rare gene fusion–previously discovered by the same researchers–that also sends mitochondria into overdrive.

“We can now expand these clinical trials to a much larger group of patients, because we can identify patients with mitochondria-driven tumors, regardless of the underlying genetics,” says Antonio Iavarone, MD, professor of neurology, who led the study with Anna Lasorella, MD, professor of pediatrics. Both are members of Columbia’s Institute for Cancer Genetics.

Study Finds Four Types of Brain Cancer

The study found that all brain cancers fall into one of four groups, including the mitochondrial subtype.

By classifying brain cancers based on their core biological features, and not just genetic alterations or cell biomarkers, the researchers have gained new insights into what drives each subtype and the prognosis for patients.

“Existing classifications for brain cancer are not informative. They don’t predict outcomes; they don’t tell us which treatments will work best,” Lasorella says.

The importance of an accurate classification system is best illustrated by the example of breast cancer. Breast cancers have very well-defined subtypes that led to the development of therapies that target the key hallmarks, such as estrogen receptors or HER2, that sustain specific subtypes.

“We feel that one of the reasons therapeutic progress in brain cancer has been so slow is because we don’t have a good way to classify these tumors,” Iavarone says.

Glioblastoma is the most common–and most lethal–primary brain tumor in adults. Median survival for individuals with glioblastoma is only 15 months.

The new study showed that glioblastoma can be classified in four biological groups. Two of them recapitulate functions active in the normal brain, either stem cells or neurons, respectively. The two other groups include mitochondrial tumors and a group of tumors with multiple metabolic activities (“plurimetabolic”) that are highly resistant to current therapies.

Patients with the mitochondrial tumors had a slightly better prognosis–and lived for a few more months–than patients with the other three types.

“We are excited about the mitochondrial group, because we have drugs for that group in clinical trials already,” Lasorella says, “but the classification now gives us ideas about how to target these other three and we are starting to investigate these more intensely.”

“We’re going beyond one mutation, one drug concept,” she says. “Sometimes it’s possible to get a response that way. But it’s time to target tumors based on the commonalities of their core biology, which can be caused by multiple different genetic combinations.”

Single-Cell Analyses Opens New View of Brain Cancer

The new findings were only possible by utilizing recent advances in single-cell analyses, which allowed the scientists to understand–cell by cell–the biological activity of thousands of cells from a single tumor.

Overall, the scientists characterized the biological properties of 17,367 individual cells from 36 different tumors.

In addition to analyzing each cell’s genetic mutations and levels of gene activity, the researchers looked at other modifications made to the cells’ genomes and the proteins and noncoding RNAs made by each cell.

Using the data, the researchers devised a computational approach to identify core biological processes, or pathways, in the cells rather than the more common approach of identifying gene signatures. “In this way, we can classify each individual tumor cell based on the real biology that sustains them,” Iavarone says.

Most tumors, the researchers found, were dominated by cells from one of the four subtypes, with a smattering of cells from the other three.

Applying Same Techniques to Other Cancers

Lasorella and Iavarone are now applying the same techniques to multiple different aggressive cancers.

This “pan-cancer” approach, they say, should identify commonalities among different types of cancer regardless of the tumor’s origin. If such common pathways exist, drugs that treat mitochondrial brain cancer may also be able to treat mitochondrial types of lung cancer, for example.

“When we classify based on the cell’s core biological activities, which all cells rely on to survive and thrive, we may find that cancers share more in common than was previously apparent by just looking at their genes,” Lasorella says.

Reference: Luciano Garofano, Simona Migliozzi, Young Taek Oh, Fulvio D’Angelo, Ryan D. Najac, Aram Ko, Brulinda Frangaj, Francesca Pia Caruso, Kai Yu, Jinzhou Yuan, Wenting Zhao, Anna Luisa Di Stefano, Franck Bielle, Tao Jiang, Peter Sims, Mario L. Suvà, Fuchou Tang, Xiao-Dong Su, Michele Ceccarelli and Marc Sanson, “Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities”, Nature Cancer, 2021

Provided by Columbia University Irving Medical Center

Unveiling The Double Origin of Cosmic Dust in the Distant Universe (Astronomy)

An international team of researchers develops a new method for the study of large, massive, dusty galaxies and sheds new light on the physical processes involved in the production of dust in these ‘giants’.

Two billion years after the Big Bang, the Universe was still very young. However, thousands of huge galaxies, rich in stars and dust, were already formed. An international study, led by SISSA – Scuola Internazionale Superiore di Studi Avanzati, now explains how this was possible. Scientists combined observational and theoretical methods to identify the physical processes behind their evolution and, for the first time, found evidence for a rapid growth of dust due to a high concentration of metals in the distant Universe. The study, published in Astronomy & Astrophysics, offers a new approach to investigate the evolutionary phase of massive objects.

Since their initial discovery 20 years ago, very distant and massive galaxies that form prodigious amount of young stars – so-called dusty (star-forming) galaxies – represent a serious challenge for astronomers: “On one hand, they are difficult to detect because they reside in dense regions of the distant Universe and contain dusty particles which absorb most of the optical light radiated by young stars”, explains Darko Donevski, postdoctoral fellow at SISSA. “On the other hand, many of these dusty ‘giants’ have been formed when the Universe was very young, sometimes even less than 1 billion years-old, and scientists have been wondering how could such large amount of dust have been produced so early in time”.

The study of these exotic objects is now possible thanks to the Atacama Large Millimeter/submillimeter Array (ALMA). This interferometer of 66 telescopes in the Atacama Desert of northern Chile is able to detect the infrared light which penetrates the dusty clouds, revealing the presence of newly forming stars. However, the origin of large amount of dust at early cosmic time is still an open question to astronomers. “Throughout many years scientists thought that production of cosmic dust was exclusively due to supernovae explosion. However, recent theoretical works suggest that dust can also grow through collisions of particles of cold, metal-rich gas which fills the galaxies,” explains the researcher.

An international team of researchers from institutions based in Europe, US, Canada and South Africa, led by Donevski, combined observational and theoretical methods to study 300 distant, dusty galaxies in order to unveil the origin of these “Giants”. In particular, they inferred the physical properties of these dusty galaxies by fitting their spectral energy distributions. “We found a huge amount of dust mass in most of our galaxies. Our estimates showed that supernovae explosions could not be responsible for all of it and a part had to be produced through particle collisions in the gaseous metal-rich environment around massive stars, as previously supposed by theoretical models” says Donevski. “This is the first time that observational data support the existence of both production mechanisms.”

Supplementary image: “Hubble space telescope (stellar emission) vs. ALMA view (dust emission) of a distant galaxy observed 11 billion years ago” (Credits: D. Donevski)

Scientists also looked at dust to star mass ratio over time to study how efficiently galaxies create and destroy dust during their evolution. “This allowed us to identify dust life cycle in two different populations of galaxies: normal, so-called ‘main-sequence’, galaxies, which are slowly evolving, and more extreme, rapidly evolving galaxies, called ‘starbursts'”, said Lara Pantoni, PhD student at SISSA, who developed the analytic model used for data interpretation. The model shows the great potential in describing differences in these two groups of observed galaxies. “Interestingly, we also showed that irrespective of their distance, stellar mass or size, compact ‘starburst’ galaxies always have dust-to-stellar mass ratio higher than the normal galaxies.”

To fully evaluate the observational findings, the team of astronomers also confronted their data with the state-of-the-art galaxy simulations. They used SIMBA, a new suite that simulates the formation and evolution of millions of galaxies since the beginning of the Universe to present time, tracking all their physical properties, including dust mass. “Up to now, theoretical models had problems in matching both galaxy dust and stellar properties simultaneously. However, our new cosmological simulation suite, SIMBA, could reproduce most of the observed data,” explains Desika Narayanan, professor of astronomy at the University of Florida and member of the DAWN institute in Copenhagen.

“Our study shows that dust production in ‘giants’ is dominated by very rapid growth of particles through their collisions with gas. Thus, it provides the first strong proof that dust formation occurs both during stars death and in the space between these massive stars, as assumed from theoretical studies,” concludes Donevski. “Moreover, it offers a new mixed approach to investigate the evolution of massive objects in the distant Universe that will be tested with future space telescopes such as the James Webb Space Telescope.”

Reference: D. Donevski, Lapi et al., “In pursuit of giants I. The evolution of the dust-to-stellar mass ratio in distant dusty galaxies”, A&A 644, A144 (2020). https://www.aanda.org/articles/aa/abs/2020/12/aa38405-20/aa38405-20.html

Provided by SISSA