Discoveries & Impact (January 2023)

Discoveries & Impact highlights select scientific discoveries across the Department of Internal Medicine...

TLT-1 is a Platelet-derived Immunosuppressor

New understanding of how cancer evades normal immune responses has paved the way for groundbreaking immunotherapies. A recent study by Tyagi et al. from Hwa Lab in the current issue of the Journal of Experimental Medicine, provides novel insights into platelet-mediated immunosuppression in cancer. The authors demonstrate that platelets from advanced stage lung cancer (NSCLC) patients are reprogrammed, leading to increased expression and release of a platelet specific protein TLT-1 (Trem like Transcript -1).

Using mice and human assays, the authors identify a platelet TLT-1–mediated immunoregulatory mechanism that drives CD8 T cell suppression. The study reveals a direct interaction between platelet-derived TLT-1 and CD3ε, present on the T cell surface, as the underlying mechanism. Interestingly, the elevated platelet TLT-1 expression corelated negatively with lung cancer patient survival, emphasizing the clinical significance of the study. Overall, the authors delineate a previously unexplored platelet-T cell crosstalk mechanism which could be important in several human diseases where T cells play a role.

Learn more in “Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells.”

Tarun Tyagi, Kanika Jain, Timur O. Yarovinsky, Michael Chiorazzi, Jing Du, Cecilia Castro, Jules Griffin, Asawari Korde, Kathleen A. Martin, Shervin S. Takyar, Richard A. Flavell, Abhijit A. Patel, John Hwa; Platelet-derived TLT-1 promotes tumor progression by suppressing CD8⁺ T cells. J Exp Med 2 January 2023; 220 (1): e20212218. doi: https://doi.org/10.1084/jem.20212218

New Model to Predict Portal Hypertension in NASH Cirrhosis

The current method of identifying patients with compensated cirrhosis, i.e. those with liver scarring due to chronic liver disease, that are at a high risk for developing clinical complications involves measuring the hepatic venous pressure gradient (HVPG). HVPG is a measure of portal pressure and HVPG ≥10 mmHg identifies clinically significant portal hypertension (CSPH). However, measuring HVPG is an invasive procedure with inherent associated risks.

A recent study led by Yale researchers Anahita Rabiee, MD, clinical fellow (digestive diseases), and Guadalupe Garcia-Tsao, MD, professor of medicine (digestive diseases), investigated noninvasive surrogate markers of CSPH. The team looked at measuring liver stiffness by transient elastography (TE), platelet count, and body mass index (BMI) in a particular population of patients with cirrhosis – those with nonalcoholic steatohepatitis (NASH) cirrhosis – and validated a model that can be used to predict the presence of CSPH in these patients. They also developed a new model that used only laboratory values to do so when TE is unavailable (FIB4plus.com)

Read more in “Noninvasive Predictors of Clinically Significant Portal Hypertension in NASH Cirrhosis: Validation of ANTICIPATE Models and Development of a Lab-Based Model.”

Rabiee A, Deng Y, Ciarleglio M, Chan JL, Pons M, Genesca J, Garcia-Tsao G. Noninvasive predictors of clinically significant portal hypertension in NASH cirrhosis: Validation of ANTICIPATE models and development of a lab-based model. Hepatol Commun. 2022 Dec;6(12):3324-3334. doi: 10.1002/hep4.2091. Epub 2022 Oct 10. PMID: 36214066; PMCID: PMC9701481.

Examining Efficacy & Safety of a Type 2 Diabetes Therapy in Patients w/ Heart Failure w/ Preserved or Mildly Reduced Ejection Fraction

Patients with prediabetes or type 2 diabetes are at an increased risk for heart failure and its associated adverse outcomes. A research team including Silvio Inzucchi, MD, professor of medicine (endocrinology), conducted an international, multicenter, double-blind, randomized, placebo-controlled trial examining the efficacy of dapagliflozin, a drug approved for type 2 diabetes treatment, in preventing worsening heart failure or cardiovascular-related mortality in patients with preserved or mildly reduced ejection fraction (a measure of how well a heart pumps blood).

In a recent paper published in The Lancet, results showed that dapagliflozin was consistently associated with improved heart failure outcomes in patients with preserved or mildly reduced ejection fraction across patient cohorts with normoglycemia, prediabetes, and type 2 diabetes. Read more in “Efficacy and Safety of Dapagliflozin in Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction by Baseline Glycaemic Status (DELIVER): A Subgroup Analysis From an International, Multicentre, Double-Blind, Randomised, Placebo-Controlled Trial.”

Inzucchi SE, Claggett BL, Vaduganathan M, Desai AS, Jhund PS, de Boer RA, Hernandez AF, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Verma S, Han Y, Kerr Saraiva JF, Bengtsson O, Petersson M, Langkilde AM, McMurray JJV, Solomon SD. Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2022 Dec;10(12):869-881. doi: 10.1016/S2213-8587(22)00308-4. Epub 2022 Nov 10. PMID: 36372069.

Metabolic Differences in Melanoma Subtypes w/ Different Anti-Tumor Immunities

The understanding of the “metabolic flexibility” of tumors - the ability of cells to adapt and select for different fuels in response to changes to the metabolic environment - has centered around the study of obesity-associated cancers. Recent work out of the Perry Lab, led by Rachel J. Perry, PhD, assistant professor of medicine (endocrinology) and cellular & molecular physiology, contributes to the mounting evidence that researchers should also be looking to immunogenic tumors not strongly associated with obesity for answers regarding nutrient competition in the tumor microenvironment.

Perry’s team compared two preclinical melanoma models to study different melanoma subtypes. The results showed that “immunologically-hot” melanoma uses more glutamine than its “immunologically-cold” counterpart, an important finding that enhances our understanding of the relationship between metabolism and immunogenicity in tumors, and may serve as a characteristic or potential target for metabolic treatment in melanoma.

Read more in “Isotope Tracing Reveals Distinct Substrate Preference in Murine Melanoma Subtypes with Differing Anti-Tumor Immunity.”

Zhang, X., Halberstam, A.A., Zhu, W. et al. Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity. Cancer Metab 10, 21 (2022). https://doi.org/10.1186/s40170...

Homeless Patient-Aligned Care Teams, a Promising Treatment Model for Veterans Experiencing Homelessness

Traditional primary care settings often do not meet the needs of people experiencing homelessness. In an article published in the Journal of General Internal Medicine, researchers reviewed existing studies on Homeless Patient-Aligned Care Teams (HPACTs), an accessible and patient-centered medical model with integrated social services for veterans experiencing homelessness in the U.S. Department of Veteran Affairs (VA) medical centers.

The team conducted a broad search and selected 26 studies for the review. The research was categorized into one of three topics: HPACT’s early implementation, association with increased quality and primary care use, or specialized programs within the HPACT framework.

Altogether, the studies suggested positive outcomes of interest, such as reductions in emergency department visits and improved patient experiences. However, the authors also identified a need for randomized controlled trials and more rigorous research methods. Addressing these gaps in the literature could increase our understanding of HPACT’s effectiveness and viability outside of VA medical centers to address homelessness more broadly. Read the review, “Primary Care for Veterans Experiencing Homelessness: a Narrative Review of the Homeless Patient Aligned Care Team (HPACT) Model.”

Tsai J, Havlik J, Howell BA, Johnson E, Rosenthal D. Primary Care for Veterans Experiencing Homelessness: a Narrative Review of the Homeless Patient Aligned Care Team (HPACT) Model. J GEN INTERN MED 2022.

Clinicians Highly Satisfied w/ Geriatric Emergency Medicine Consult Model

A Geriatric Medicine consultation service can support emergency department (ED) clinicians in creating comprehensive patient care plans for older adults. The Geriatric Emergency Medicine service (GEMs) is a team of advanced practice registered nurses (APRN) who are specially trained to identify challenges to older adults. The GEMs team works closely with ED clinicians to create discharge plans for patients who will be admitted and provides recommendations for avoidable hospital-related complications. A recent study demonstrates that an APRN-led GEMs program is well-received among ED clinicians.

Out of survey respondents, more than 85 percent of ED clinicians indicated they were “extremely satisfied” with the GEMs program. In addition, respondents identified valuable clinical insights of GEMs, such as fall-related injuries and symptoms of dementia. Most clinicians also felt that the consultation changed the final care plan. These findings also suggest GEMs can address challenges in the emergency department related to increased patient volume and limited time resources. Read more about their responses in the Journal of the American Geriatrics Society.

Moreines LT, Gettel CJ, Hajduk AM, Kukulka S, Lai JM, Ouellet JA. Emergency department clinician satisfaction with an APRN-led geriatric emergency medicine service consult team. J Am Geriatr Soc 2022. doi.org/10.1111/jgs.18133

Longer-Term Results of Luspatercept Trial Shows Greater Benefits for Patients w/ Myelodysplastic Syndromes

Luspatercept, a medication used to treat anemia in certain diseases including myelodysplastic syndromes, was approved in the U.S. and Europe based on the phase 3, double-blind MEDALIST study showing the drug’s benefit in helping patients achieve red blood cell transfusion independence (RBC-TI). Chronic RBC transfusions are associated with increased medical risks, reduced survival, and decreased quality of life.

Longer-term results of the study, led in part by Amer Zeidan, MBBS, MHS, associate professor of medicine (hematology), showed additional benefits for patients in double the initial follow-up time used for the primary analysis. Results showed approximately three times as many patients in the trial receiving luspatercept rather than placebo achieved RBC-TI for 8 weeks or greater during the initial 48 weeks of the trial. Additional results showed a higher percentage of patients receiving luspatercept achieved RBC-TI for 8 or more weeks, indicating additional patients achieve RBC-TI outside the initial 24-week follow-up period.

The analysis also shows continued clinically meaningful benefit among patients with high transfusion burden, who are among the most challenging to treat, as well as significant reduction in transfusion burden.

The study demonstrates the safety and efficacy of the drug in reducing transfusion burden and maintaining or improving quality of life in these patients. Importantly, the work also found continued clinically meaningful benefit among patients with high transfusion burden, who are among the most challenging to treat. Read more in “Longer-Term Benefit of Luspatercept in Transfusion-Dependent Lower-Risk Myelodysplastic Syndromes with Ring Sideroblasts.”

Amer M. Zeidan, Uwe Platzbecker, Guillermo Garcia-Manero, Mikkael A. Sekeres, Pierre Fenaux, Amy E. DeZern, Peter L. Greenberg, Michael R. Savona, Joseph G. Jurcic, Amit K. Verma, Ghulam J. Mufti, Rena Buckstein, Valeria Santini, Jeevan K. Shetty, Rodrigo Ito, Jennie Zhang, George Zhang, Xianwei Ha, Jay T. Backstrom, Rami S. Komrokji; Longer-term benefit of luspatercept in transfusion-dependent lower-risk myelodysplastic syndromes with ring sideroblasts. Blood 2022; 140 (20): 2170–2174. doi: https://doi.org/10.1182/blood....

New Data Shows Importance of Podocyte Histone Deacetylases in Kidney Development

Previous research has demonstrated the importance of podocyte (specialized kidney cells) histone deacetylases (HDAC; specialized enzymes) in maintaining the filtration barrier that allows kidneys to filter blood appropriately. A new study led by Paulina Medina Rangel, PhD, postdoctoral associate, in the lab of Shuta Ishibe, MD, professor of medicine (nephrology), examined the importance of podocyte-specific HDACs during development.

Researchers generated a preclinical model that did not express podocyte-specific Hdac1 and 2. Results found high levels of protein in the urine, progressive kidney failure, and histological features of collapsing glomerulopathy. Furthermore, podocyte DNA damage due to lack of these enzymes led to cell-cycle arrest, senescence, and podocyte detachment and loss. The work has demonstrated the essential role that these enzymes play in developing and maintaining the integrity of the glomerular filtration barrier.

Read more in “Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2.”

Medina Rangel P, Cross E, Liu C, Pedigo C, Tian X, Guitierrez-Calabres E, Nagata S, Priyadarshini A, Lerner G, Bunda P, Perincheri S, Gu J, Zhao H, Wang Y, Inoue K, Ishibe S. Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2. J Am Soc Nephrol. 2022 Nov 22:ASN.2022050598. doi: 10.1681/ASN.2022050598. Epub ahead of print. PMID: 36414418.

Who Decides? The Complicated Issue of ICU Admissions

In an editorial in Annals of the American Thoracic Society, Yale author Snigdha Jain, MD, MHS, and her colleague, Thomas S. Valley, MD, MSc, of Michigan Medicine, discuss admissions to intensive care units (ICUs) in the U.S. when hospital conditions are strained, as they have been during the COVID-19 pandemic. The authors comment on a study in the same journal issue that tests the hypothesis that strained hospitals might exclude certain racial or ethnic groups from ICU care more than others among patients hospitalized for sepsis or acute respiratory failure at two large healthcare systems.

The authors conclude that “the messy system that we currently use to decide who receives ICU care is problematic.” Read the editorial here.

Jain S, Valley TS. Who Receives ICU Care during Times of Strain? Triage and the Potential for Racial Disparities. Ann Am Thorac Soc. 2022 Dec;19(12):1973-1974. doi: 10.1513/AnnalsATS.202209-766ED. PMID: 36454169; PMCID: PMC9743470.