bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racialized Economic Segregation and Breast Cancer Mortality among Women in Maryland
Authors: Connor Avonne E. , Kaur Maneet , Dibble Kate E. , Visvanathan Kala , Dean Lorraine T. , Hayes Jennifer H. 
Published: December 2021

Abstract

Background:
Our objective was to determine the association between racialized economic segregation and the hazard of breast cancer mortality in Maryland.

Methods:
Among 35,066 women (24,540 White; 10,526 Black) diagnosed with incident invasive breast cancer in Maryland during 2007 to 2017, exposure to racialized economic segregation was measured at the census tract level using Index of Concentration at the Extremes metrics. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression for the association between racialized economic segregation and the hazard of breast cancer mortality, accounting for clustering at the census tract level. Models were adjusted for age and stratified by race, median age (&lt;60 years, ≥60 years), and clinical characteristics.

Results:
Overall, the hazard of breast cancer mortality was 1.84 times as high (95% CI, 1.64–2.06) for the least privileged quintile of racialized economic segregation compared with the most privileged quintile. This association differed significantly (Pinteraction&lt; 0.05) by race and age, with 1.20 (95% CI, 0.90–1.60) times the hazard of breast cancer mortality for Black women versus 1.66 (95% CI, 1.41–1.95) times the hazard for White women, and with greater hazards for younger women (HR, 2.17; 95% CI, 1.83–2.57) than older women (HR, 1.62; 95% CI, 1.40–1.88).

Conclusions:
Our results suggest that breast cancer survival disparities exist in Maryland among women residing in the least privileged census tracts with lower income households and higher proportions of Black residents.

Impact:
Our findings provide new insights into the breast cancer mortality disparities observed among women in Maryland.
Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia
Authors: Stein Eytan M. , DeAngelo Daniel J. , Chromik Jörg , Chatterjee Manik , Bauer Sebastian , Lin Chia-Chi , Suarez Cristina , de Vos Filip , Steeghs Neeltje , Cassier Philippe A. , Tai David , Kiladjian Jean-Jacques , Yamamoto Noboru , Mous Rogier , Esteve Jordi , Minami Hironobu , Ferretti Stephane , Guerreiro Nelson , Meille Christophe , Radhakrishnan Rajkumar , Pereira Bernard , Mariconti Luisa , Halilovic Ensar , Fabre Claire , Carpio Cecilia 
Published: December 2021

Abstract

Purpose:
This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53–MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers.

Patients and Methods:
Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5–350 mg) and 2A (days 1–14; 28-day cycle; dose 1–20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1–7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1.

Results:
Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2–27.4] in solid tumors and 4.2% (95% CI, 0.1–21.1), 20% (95% CI, 4.3–48.1), and 22.2% (95% CI, 8.6–42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively.

Conclusions:
A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.
Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study
Authors: Taylor Matthew H. , Betts Courtney B. , Maloney Lauren , Nadler Eric , Algazi Alain , Guarino Michael J. , Nemunaitis John , Jimeno Antonio , Patel Priti , Munugalavadla Veerendra , Tao Lin , Adkins Douglas , Goldschmidt Jerome H. , Cohen Ezra E.W. , Coussens Lisa M. 
Published: December 2021

Abstract

Purpose:
Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.

Patients and Methods:
Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.

Results:
Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.

Conclusions:
Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.
Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma
Authors: Piper Miles , Van Court Benjamin , Mueller Adam , Watanabe Shuichi , Bickett Thomas , Bhatia Shilpa , Darragh Laurel B. , Mayeda Max , Nguyen Diemmy , Gadwa Jacob , Knitz Michael , Corbo Sophia , Morgan Rustain , Lee Jung-Jae , Dent Alexander , Goodman Karyn , Messersmith Wells , Schulick Richard , Del Chiaro Marco , Zhu Yuwen , Kedl Ross M. , Lenz Laurel , Karam Sana D. 
Published: December 2021

Abstract

Purpose:
Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.

Experimental Design:
PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations.

Results:
We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets.

Conclusions:
Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.
Abstract P244: NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC
Authors: Tangpeerachaikul Anupong , Deshpande Amit , Kohl Nancy E. , Horan Joshua C. , Pelish Henry E. 
Published: December 2021

Abstract
ALK receptor tyrosine kinase can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. ALK rearrangements are detected in up to 5% of advanced non-small cell lung cancer (NSCLC), and up to 40% of patients present with brain metastases at diagnosis. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved tyrosine kinase inhibitors for ALK-positive NSCLC. However, durability of response to these treatments is partly limited by mutations in ALK that confer resistance. The G1202R solvent front mutation is commonly observed in patients that have progressed on crizotinib, ceritinib, alectinib, or brigatinib. Patients with tumors harboring G1202R have responded to lorlatinib, but many have relapsed after acquiring compound mutations such as G1202R/L1196M and G1202R/G1269A. Another challenge with lorlatinib is central nervous system (CNS) adverse events attributed to inhibition of tropomyosin receptor kinase B (TRKB), a kinase structurally related to ALK. NVL-655 is a novel preclinical brain-penetrant ALK inhibitor with selectivity over TRKB. We previously reported that NVL-655 inhibits ALK G1202R, G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F in vitro; has favorable kinome and ALK-vs-TRKB selectivity profiles; and shows antitumor activity in a Ba/F3 EML4-ALK variant 1 (v1) G1202R/L1196M xenograft model. Here we report results of a broader preclinical characterization of NVL-655 across ALK models, including an intracranial model. NVL-655 was observed to induce regression in a HIP1-ALK patient-derived xenograft model, an EML4-ALK v1 human cancer cell line-derived model (NCI-H3122), and Ba/F3 xenograft models expressing EML4-ALK v1 G1202R and G1202R/G1269A. Pharmacodynamic (PD) biomarker analyses supported in vivo ALK inhibition by NVL-655. Furthermore, NVL-655 was observed to reduce tumor size and prolong survival by more than 4-fold in a mouse intracranial tumor model of Ba/F3 EML4-ALK v1 G1202R/L1196M luciferase. In conclusion, NVL-655 has a preclinical profile that we believe supports its potential to address a medical need for patients with ALK-positive disease, including those with G1202R compound mutations. We believe the findings presented here support the evaluation of NVL-655 for the treatment of patients with ALK-driven disease.
Citation Format: Anupong Tangpeerachaikul, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P244.
Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Authors: Garciaz Sylvain , Guirguis Andrew A. , Müller Sebastian , Brown Fiona C. , Chan Yih-Chih , Motazedian Ali , Rowe Caitlin L. , Kuzich James A. , Chan Kah Lok , Tran Kevin , Smith Lorey , MacPherson Laura , Liddicoat Brian , Lam Enid Y.N. , Cañeque Tatiana , Burr Marian L. , Litalien Véronique , Pomilio Giovanna , Poplineau Mathilde , Duprez Estelle , Dawson Sarah-Jane , Ramm Georg , Cox Andrew G. , Brown Kristin K. , Huang David C.S. , Wei Andrew H. , McArthur Kate , Rodriguez Raphaël , Dawson Mark A. 
Published: December 2021

Abstract

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.

Significance:
Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia.
This article is highlighted in the In This Issue feature, p. 587
Amygdala in Action: Functional Connectivity during Approach and Avoidance Behaviors
Authors: Leitão Joana , Burckhardt Maya , Vuilleumier Patrik 
Published: December 2021

AbstractMotivation is an important feature of emotion. By driving approach to positive events and promoting avoidance of negative stimuli, motivation drives adaptive actions and goal pursuit. The amygdala has been associated with a variety of affective processes, particularly the appraisal of stimulus valence that is assumed to play a crucial role in the generation of approach and avoidance behaviors. Here, we measured amygdala functional connectivity patterns while participants played a video game manipulating goal conduciveness through the presence of good, neutral, or bad monsters. As expected, good versus bad monsters elicited opposing motivated behaviors, whereby good monsters induced more approach and bad monsters triggered more avoidance. These opposing directional behaviors were paralleled by increased connectivity between the amygdala and medial brain areas, such as the OFC and posterior cingulate, for good relative to bad, and between amygdala and caudate for bad relative to good monsters. Moreover, in both conditions, individual connectivity strength between the amygdala and medial prefrontal regions was positively correlated with brain scores from a latent component representing efficient goal pursuit, which was identified by a partial least squares analysis determining the multivariate association between amygdala connectivity and behavioral motivation indices during gameplay. At the brain level, this latent component highlighted a widespread pattern of amygdala connectivity, including a dorsal frontoparietal network and motor areas. These results suggest that amygdala-medial prefrontal interactions captured the overall subjective relevance of ongoing events, which could consecutively drive the engagement of attentional, executive, and motor circuits necessary for implementing successful goal-pursuit, irrespective of approach or avoidance directions.
Phyllagathis chongzuoensis (Melastomataceae), a new species from Guangxi, China
Authors: ZHANG ZHE , TU XIONG-DE , YAO SHI-WEI , MA LIANG , ZENG SI-JIN 
Published: December 2021

Phyllagathis chongzuoensis, a new species from Guangxi Province, China, is described here. It is similar to P. erecta in having stiffly papery leaf blades with abaxially furfuraceous indumentum, similar leaf vernation, umbellate paniculate inflorescences and cup-shaped capsules, but differs in stoloniferous stem with indistinct internodes, shorter petioles, and obovate to suborbicular leaf blades with irregularly denticulate margin. Phylogenetic analyses based on nrITS and plastid genome confirmed that it is close to P. erecta.
A Comparison of Factors That Led to the Extreme Sea Ice Minima in the Twenty-First Century in the Arctic Ocean
Authors: Liang Xi , Li Xichen , Bi Haibo , Losch Martin , Gao Yongqi , Zhao Fu , Tian Zhongxiang , Liu Chengyan 
Published: December 2021

Abstract
The extreme Arctic sea ice minima in the twenty-first century have been attributed to multiple factors, such as anomalous atmospheric circulation, excess solar radiation absorbed by open ocean, and thinning sea ice in a warming world. Most likely it is the combination of these factors that drives the extreme sea ice minima, but how the factors rank in setting the conditions for these events has not been quantified. To address this question, the sea ice budget of an Arctic regional sea ice–ocean model forced by atmospheric reanalysis data is analyzed to assess the development of the observed sea ice minima. Results show that the ice area difference in the years 2012, 2019, and 2007 is driven to over 60% by the difference in summertime sea ice area loss due to air–ocean heat flux over open water. Other contributions are small. For the years 2012 and 2020 the situation is different and more complex. The air–ice heat flux causes more sea ice area loss in summer 2020 than in 2012 due to warmer air temperatures, but this difference in sea ice area loss is compensated by reduced advective sea ice loss out of the Arctic Ocean mainly caused by the relaxation of the Arctic dipole. The difference in open water area in early August leads to different air–ocean heat fluxes, which distinguishes the sea ice minima in 2012 and 2020. Further, sensitivity experiments indicate that both the atmospheric circulation associated with the Arctic dipole and extreme storms are essential conditions for a new low record of sea ice extent.
Country Participation in the WHO Framework Convention on Tobacco Control Health Warnings Database
Authors: Seitz Christopher M. , Ward Kenneth D. , Kabir Zubair 
Published: December 2021

Background The World Health Organization’s (WHO) Framework Convention on Tobacco Control (FCTC) Health Warnings Database is an online, publicly available resource created for countries to upload and share pictorial health warnings for tobacco packaging. The purpose of this study was to evaluate the extent to which the database is used by countries for the sharing of pictorial warnings. Methods The study’s sample included parties to the FCTC who required graphic health warning labels on cigarette packaging from. Those countries were categorized as having a low, middle, and high Socio-Demographic Index (SDI). The Health Warnings Database was then analyzed for those countries’ unique pictorial images, as well as the number of pictorials that were shared between countries. Results Of the 110 countries that required pictorial warnings on cigarette packaging, only 53 (48%) voluntarily contributed pictorials to the database, with most of those (53%) being high SDI-level countries. There were 342 unique pictorials on the database, with 62 images posted by seven countries that were used by 13 other countries. Conclusion While sharing was evident from the database, there remains a need for more countries to upload the pictorials to the database. There is also a need to expand the database to include alternative tobacco products, such as waterpipe tobacco and e-cigarettes.
Methenamine for Recurrent Urinary Tract Infections in Solid Organ Transplantation
Authors: Sweiss Helen , Bhayana Suverta , Hall Reed , Nelson Joelle , Kincaide Elisabeth 
Published: December 2021

Introduction Recurrent urinary tract infections remain a challenge in solid organ transplant and have a negative impact on morbidity/mortality. Project Aim The purpose of this program evaluation was to determine the impact of methenamine on recurrent urinary tract infection in kidney and liver-kidney transplant recipients. Design This retrospective review included patients > 18 years of age who received a kidney or liver-kidney transplant. Patients were divided into the following groups: (1) Methenamine therapy initiation received methenamine for ≥ 180 days or (2) Non-methenamine therapy: did not receive recurrent urinary tract infection prophylaxis. A total of 60 patients were included. Results When comparing outcomes between methenamine therapy initiation and non-methenamine therapy group, a significant reduction in the rate of recurrent urinary tract infection was reported in the methenamine therapy initiation group (0.6 vs 1.3 per 180 patient days follow-up, P = 0.0005). A significant reduction was also noted with rate of asymptomatic bacteriuria, treatment failures, bacteremia, hospitalizations due to recurrent urinary tract infection, multi-drug resistant organism isolated, and the average duration of antibiotic use. A significant difference in the time to failure of methenamine therapy initiation versus non-methenamine therapy is noted up to 180 patient-days follow-up (RR 1.56, P = 0.0019). Conclusion This evaluation supported methenamine therapy for recurrent urinary tract infection in kidney and liver-kidney transplant. The most significant impact of methenamine recurrent urinary tract infection was seen in the first 30 days after initiation.