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Article ; Online: Ceg1 depletion reveals mechanisms governing degradation of non-capped RNAs in Saccharomyces cerevisiae.

Zanin, Onofrio / Eastham, Matthew / Winczura, Kinga / Ashe, Mark / Martinez-Nunez, Rocio T / Hebenstreit, Daniel / Grzechnik, Pawel

Communications biology

2023 Volume 6, Issue 1, Page(s) 1112

Abstract: Most functional eukaryotic mRNAs contain a 5' 7-methylguanosine (m ...

Abstract	Most functional eukaryotic mRNAs contain a 5' 7-methylguanosine (m
MeSH term(s)	Exonucleases/metabolism ; RNA Caps/genetics ; RNA Caps/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Exonucleases (EC 3.1.-) ; RNA Caps ; RNA, Messenger ; Saccharomyces cerevisiae Proteins ; mRNA guanylyltransferase (EC 2.7.7.50)
Language	English
Publishing date	2023-11-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05495-6
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Article: Role of PSMA PET-guided metastases-directed therapy in oligometastatic recurrent prostate cancer.

Alberto, Matthew / Yim, Arthur / Papa, Nathan / Siva, Shankar / Ischia, Joseph / Touijer, Karim / Eastham, James A / Bolton, Damien / Perera, Marlon

Frontiers in oncology

2022 Volume 12, Page(s) 929444

Abstract: Oligometastatic prostate cancer (OMPC) has been proposed as an intermediary state between localised disease and widespread metastases, with varying definitions including 1, 3, or ≤5 visceral or bone metastasis. Traditional definitions of OMPC are based ... ...

Abstract	Oligometastatic prostate cancer (OMPC) has been proposed as an intermediary state between localised disease and widespread metastases, with varying definitions including 1, 3, or ≤5 visceral or bone metastasis. Traditional definitions of OMPC are based on staging with conventional imaging, such as computerised tomography (CT) and whole-body bone scan (WBBS). Novel imaging modalities such as prostate-specific membrane antigen positron emission tomography (PSMA PET) have improved diagnostic utility in detecting early metastatic prostate cancer (PC) metastases compared with conventional imaging. Specifically, meta-analytical data suggest that PSMA PET is sensitive in detecting oligometastatic disease in patients with biochemical recurrence (BCR) post-radical treatment of PC. Recent trials have evaluated PSMA PET-guided metastases-directed therapy (MDT) in oligometastatic recurrent disease, typically with salvage surgery or radiotherapy (RT). To date, these preliminary studies demonstrate promising results, potentially delaying the need for systemic therapy. We aim to report a comprehensive, multidisciplinary review of PSMA-guided MDT in OMPC. In this review, we highlight the utility of PMSA PET in biochemically recurrent disease and impact of PSMA PET on the definition of oligometastatic disease and outline data pertaining to PSMA-guided MDT.
Language	English
Publishing date	2022-08-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.929444
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Article ; Online: Mortality Risk for Docetaxel-Treated, High-Grade Prostate Cancer With Low PSA Levels: A Meta-Analysis.

Mahal, Brandon A / Kwak, Lucia / Xie, Wanling / Eastham, James A / James, Nicholas D / Sandler, Howard M / Feng, Felix Y / Brihoum, Meryem / Fizazi, Karim / Sweeney, Christopher / Ravi, Praful / D'Amico, Anthony V

JAMA network open

2023 Volume 6, Issue 11, Page(s) e2340787

Abstract: Importance: Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm.: Objective: To assess for these patients whether adding ... ...

Abstract	Importance: Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm. Objective: To assess for these patients whether adding docetaxel to standard of care (SOC) treatment is associated with decreased prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM). Data sources: PubMed search from 2000 to 2022. Study selection: Five prospective randomized clinical trials (RCTs) performed in the US, France, and the United Kingdom evaluating SOC treatment with radiotherapy and androgen deprivation therapy (ADT) or with radical prostatectomy vs SOC plus docetaxel. Data extraction and synthesis: Individual data were included from patients with nonmetastatic prostate cancer, a PSA level of less than 4 ng/mL, and a Gleason score of 8 to 10. Patients initiated treatment between February 21, 2006, and December 31, 2015 (median follow-up, 7.1 [IQR, 5.4-9.9] years). Data were analyzed on December 16, 2022. Main outcomes and measures: Hazard ratio (HR) of ACM and subdistribution HR (sHR) of PCSM adjusted for performance status (1 vs 0 or good health), Gleason score (9 or 10 vs 8), tumor category (T3-T4 vs T1-T2 or TX), and duration of ADT (2 years vs 4-6 months). Results: From a cohort of 2184 patients, 145 patients (6.6%) in 4 RCTs were eligible (median age, 63 [IQR, 46-67] years). Thirty-one patients died, and of these deaths, 22 were due to prostate cancer. Performance status was 0 for 139 patients (95.9%) and 1 for 6 patients (4.1%). A reduced but nonsignificant risk of ACM (HR, 0.51 [95% CI, 0.24-1.09]) and PCSM (sHR, 0.42 [95% CI, 0.17-1.02]) was associated with patients randomized to SOC plus docetaxel compared with SOC. The risk reduction in ACM (HR, 0.46 [95% CI, 0.21-1.02]) was more pronounced among patients with a performance status of 0 and was significant for PCSM (sHR, 0.30 [95% CI, 0.11-0.86]). Conclusions and relevance: Adding docetaxel to SOC treatment for patients who are in otherwise good health with a PSA level of less than 4 ng/mL and a Gleason score of 8 to 10 was associated with a significant reduction in PCSM and therefore has the potential to improve prognosis.
MeSH term(s)	Male ; Humans ; Middle Aged ; Docetaxel/therapeutic use ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy ; Prostate ; Prostatectomy ; Randomized Controlled Trials as Topic
Chemical Substances	Docetaxel (15H5577CQD) ; Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2023-11-01
Publishing country	United States
Document type	Meta-Analysis ; Journal Article
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2023.40787
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Article ; Online: XIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death.

Witt, Axel / Goncharov, Tatiana / Lee, Yujung Michelle / Kist, Matthias / Dohse, Monika / Eastham, Jeff / Dugger, Debra / Newton, Kim / Webster, Joshua D / Vucic, Domagoj

Cell death & disease

2023 Volume 14, Issue 4, Page(s) 262

Abstract: XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn's disease, or those needing allogeneic ... ...

Abstract	XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn's disease, or those needing allogeneic hematopoietic cell transplantation, is associated with a worse prognosis. In this study, we show that XIAP absence sensitizes cells and mice to LPS- and TNF-mediated cell death without affecting LPS- or TNF-induced NF-κB and MAPK signaling. In XIAP deficient mice, RIP1 inhibition effectively blocks TNF-stimulated cell death, hypothermia, lethality, cytokine/chemokine release, intestinal tissue damage and granulocyte migration. By contrast, inhibition of the related kinase RIP2 does not affect TNF-stimulated events, suggesting a lack of involvement for the RIP2-NOD2 signaling pathway. Overall, our data indicate that in XIAP's absence RIP1 is a critical component of TNF-mediated inflammation, suggesting that RIP1 inhibition could be an attractive option for patients with XIAP deficiency.
MeSH term(s)	Animals ; Mice ; Lipopolysaccharides/pharmacology ; Lymphoproliferative Disorders ; NF-kappa B/metabolism ; Signal Transduction ; Tumor Necrosis Factors/metabolism
Chemical Substances	Lipopolysaccharides ; NF-kappa B ; Birc4 protein, mouse ; Ralbp1 protein, mouse ; Tumor Necrosis Factors
Language	English
Publishing date	2023-04-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-05793-1
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Article ; Online: The Commit to Be Fit framework: a community case study of a multi-level, holistic school-based wellness initiative in rural Virginia.

Redelfs, Alisha H / Smith, Madeleine / Merrill, Jacinda A / Grimsley, Shannon / Jenkins, Hollyann E / Tederick, Jacqueline S / Butler, Amanda G / Dueck, Kirsten / Eastham Thomas, Margy / Perez, David A / Whigham, Leah D

Frontiers in public health

2023 Volume 11, Page(s) 1067454

Abstract: Background: Public health interventions that target children's physical, mental, and emotional health will enhance their ability to learn and grow. Although more complex, school initiatives that address multiple ecological levels and take a holistic ... ...

Abstract	Background: Public health interventions that target children's physical, mental, and emotional health will enhance their ability to learn and grow. Although more complex, school initiatives that address multiple ecological levels and take a holistic view may be more effective and likely to lead to lasting change. Aims: This article presents the framework of Commit to Be Fit (C2BF) as an example of how schools can integrate multi-level and holistic approaches for health. This innovative school-based intervention includes activities addressing individual, home, school, and community to create a culture of wellness. We describe the implementation of C2BF and its basis in ecological models and give examples of activities across three components: cafeteria, classroom, and community. We discuss challenges and note that leadership engagement and alignment were critical elements for C2BF's success thus far. Discussion: C2BF uses a school-based multi-level approach to creating a culture of wellness and holistic health for students, teachers, and community members. C2BF is unique compared to other school-based programming and includes activities that address all eight domains posited for program sustainability within public health. Built to be flexible and adaptive, C2BF was able to successfully pivot during the COVID pandemic and also follow new science. Conclusion: C2BF and other multi-level holistic approaches are more likely to achieve long-term change by utilizing strategies across the multiple levels of the ecological model to improve health and wellbeing.
MeSH term(s)	Child ; Humans ; COVID-19/epidemiology ; COVID-19/prevention & control ; Holistic Health ; Virginia ; Emotions ; Leadership
Language	English
Publishing date	2023-08-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2711781-9
ISSN	2296-2565 ; 2296-2565
ISSN (online)	2296-2565
ISSN	2296-2565
DOI	10.3389/fpubh.2023.1067454
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Article: Comparison of salvage radical prostatectomy vs. salvage ablation therapy for biopsy-proven radio-recurrent localized prostate cancer.

McPherson, Victor / Nair, Shiva M / Tin, Amy L / Dewar, Malcolm / Siddiqui, Khurram / Sjoberg, Daniel D / Vickers, Andrew J / Eastham, James / Chin, Joseph L

Canadian Urological Association journal = Journal de l'Association des urologues du Canada

2023 Volume 18, Issue 2, Page(s) 41–46

Abstract: Introduction: Radiation therapy for prostate cancer is associated with a 15-20% five-year recurrence rate. Patients with recurrence in the prostate only are candidates for salvage local therapies; however, there is no consensus on modality. This study ... ...

Abstract	Introduction: Radiation therapy for prostate cancer is associated with a 15-20% five-year recurrence rate. Patients with recurrence in the prostate only are candidates for salvage local therapies; however, there is no consensus on modality. This study uses registries at Memorial Sloan Kettering Cancer Center (MSKCC) and University of Western Ontario (UWO) to compare the oncologic outcomes of salvage radical prostatectomy (SRP) and salvage ablation (SA). Methods: A total of 444 patients were available for analysis. Due to intergroup differences, propensity score methodology was used and identified 378 patients with more comparable pre-salvage prostate-specific antigen (PSA), Gleason score, and primary radiation treatment. Patients underwent SRP at MSKCC and SA at UWO. Results: Of the 378 patients, 48 died of disease, with a 6.0-year median (interquartile range [IQR] 3.0, 9.7) followup among survivors; 88 developed metastases, with a median 4.6-year (IQR 2.3, 7.9) followup among metastasis-free survivors. There was a non-significantly higher rate of cancer-specific (hazard ratio [HR ] 1.02, 95% confidence interval [CI] 0.51, 2.06, p=0.9) and improved metastasis-free survival (HR 0.71, 95% CI 0.44, 1.13, p=0.15) among patients undergoing SA compared to patients undergoing SRP. There were 143 patients who received hormonal therapy, with higher rates of androgen deprivation therapy (ADT) in SA (HR 1.42, 95% CI 0.97, 2.08, p=0.068), although this did not meet conventional levels of significance. Conclusions: This propensity score analysis of salvage therapy for radio-recurrent prostate cancer identified no statistically significant differences in oncologic outcome between SRP and SA; however, there was evidence of a lower risk of ADT in the cohort undergoing SRP. Given they are both potentially curative therapies, these treatments are viable options for men with clinically localized, radio-recurrent prostate cancer rather than ADT alone. Future research may further elucidate subpopulations that may be more amenable to either SRP or SA.
Language	English
Publishing date	2023-11-12
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2431403-1
ISSN	1911-6470
ISSN	1911-6470
DOI	10.5489/cuaj.8373
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Article: NASA GEOS Composition Forecast Modeling System GEOS-CF v1.0: Stratospheric Composition.

Knowland, K E / Keller, C A / Wales, P A / Wargan, K / Coy, L / Johnson, M S / Liu, J / Lucchesi, R A / Eastham, S D / Fleming, E / Liang, Q / Leblanc, T / Livesey, N J / Walker, K A / Ott, L E / Pawson, S

Journal of advances in modeling earth systems

2022 Volume 14, Issue 6, Page(s) e2021MS002852

Abstract: The NASA Goddard Earth Observing System (GEOS) Composition Forecast (GEOS-CF) provides recent estimates and 5-day forecasts of atmospheric composition to the public in near-real time. To do this, the GEOS Earth system model is coupled with the GEOS-Chem ... ...

Abstract	The NASA Goddard Earth Observing System (GEOS) Composition Forecast (GEOS-CF) provides recent estimates and 5-day forecasts of atmospheric composition to the public in near-real time. To do this, the GEOS Earth system model is coupled with the GEOS-Chem tropospheric-stratospheric unified chemistry extension (UCX) to represent composition from the surface to the top of the GEOS atmosphere (0.01 hPa). The GEOS-CF system is described, including updates made to the GEOS-Chem UCX mechanism within GEOS-CF for improved representation of stratospheric chemistry. Comparisons are made against balloon, lidar, and satellite observations for stratospheric composition, including measurements of ozone (O
Language	English
Publishing date	2022-06-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2462132-8
ISSN	1942-2466
ISSN	1942-2466
DOI	10.1029/2021MS002852
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Article ; Online: Trauma Surgeons' Perceptions of Resuscitating Lethally Injured Patients for Organ Preservation.

Peetz, Allan / Kuzemchak, Marie / Hammack, Catherine / Guillamondegui, Oscar D / Dennis, Bradley M / Eastham, Shannon / Meador, Keith / Beskow, Laura / Patel, Mayur

The American surgeon

2021 Volume 88, Issue 4, Page(s) 663–667

Abstract: Background: Trauma surgeons face a challenge when deciding whether to resuscitate lethally injured patients whose organ donor status is unknown. Data suggests practice pattern variability in this setting, but little is known about why.: Materials and ... ...

Abstract	Background: Trauma surgeons face a challenge when deciding whether to resuscitate lethally injured patients whose organ donor status is unknown. Data suggests practice pattern variability in this setting, but little is known about why. Materials and methods: We conducted semi-structured interviews with trauma surgeons practicing in Level 1 or 2 trauma centers in Tennessee. Interviews focused on ethical dilemmas and resource constraints. Analysis was performed using inductive thematic analysis. Results: Response rate was 73% (11/15). Four key themes emerged. All described resuscitating patients to buy time to collect more definitive clinical information and to identify family. Some acknowledged this served the secondary purpose of organ preservation. 11/11 participants felt a primacy of obligation to the patient in front of them even after it became apparent, they could not personally benefit. For 9/11 (82%), the moral obligation to consider organ preservation was secondary/balancing; 2/11 (18%) felt it was irrelevant/immoral. Resource allocation was commonly considered. All participants expressed some limitation to resources they would allocate. All participants conveyed clear moral agency in determining resuscitation extent when the goal was to save the patient's life, however this was less clear when resuscitating for organ preservation. Across themes, perceptions of a "standard practice" existed but the described practices were not consistent across interviewees. Discussion: Widely ranging perceptions regarding ethical and resource considerations underlie practices resuscitating toward organ preservation. Common themes suggest a lack of consensus. Despite expressed beliefs, there is no identifiable standard of practice amongst trauma surgeons resuscitating in this setting.
MeSH term(s)	Humans ; Motivation ; Organ Preservation ; Resuscitation ; Surgeons ; Trauma Centers
Language	English
Publishing date	2021-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	202465-2
ISSN	1555-9823 ; 0003-1348
ISSN (online)	1555-9823
ISSN	0003-1348
DOI	10.1177/00031348211065100
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Article ; Online: Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity.

Cell metabolism

2023 Volume 35, Issue 7, Page(s) 1132–1146.e9

Abstract: Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 ( ... ...

Abstract	Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity.
MeSH term(s)	Humans ; Canagliflozin/pharmacology ; Canagliflozin/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy ; Autoimmunity ; T-Lymphocytes ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Autoimmune Diseases/drug therapy ; Hypoglycemic Agents/pharmacology
Chemical Substances	Canagliflozin (0SAC974Z85) ; Sodium-Glucose Transporter 2 Inhibitors ; Hypoglycemic Agents
Language	English
Publishing date	2023-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2023.05.001
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Article ; Online: Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.

Sumiyoshi, Takayuki / Wang, Xiaofei / Warner, Evan W / Sboner, Andrea / Annala, Matti / Sigouros, Michael / Beja, Kevin / Mizuno, Kei / Ku, Shengyu / Fazli, Ladan / Eastham, James / Taplin, Mary-Ellen / Simko, Jeffrey / Halabi, Susan / Morris, Michael J / Gleave, Martin E / Wyatt, Alexander W / Beltran, Himisha

Journal of the National Cancer Institute

2023 Volume 116, Issue 1, Page(s) 115–126

Abstract: Background: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical ... ...

Abstract	Background: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. Methods: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. Results: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. Conclusions: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy.
MeSH term(s)	Male ; Humans ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/surgery ; Neoadjuvant Therapy ; Docetaxel ; Androgen Antagonists/therapeutic use ; Androgens/therapeutic use ; Treatment Outcome ; Neoplasm Recurrence, Local/surgery ; Prostate-Specific Antigen ; Prostatectomy ; Nuclear Proteins ; Repressor Proteins
Chemical Substances	Docetaxel (15H5577CQD) ; Androgen Antagonists ; Androgens ; Prostate-Specific Antigen (EC 3.4.21.77) ; SPOP protein, human ; Nuclear Proteins ; Repressor Proteins
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djad184
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