bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Rheic riddle: ocean closed, but no orogen
Authors: Franke Wolfgang 
Published: June 2023

Abstract
Although the Rheic Ocean was the widest to be closed during the assembly of Pangaea, its suture zone is dominated by a younger (Rhenohercynian) Wilson Cycle. The present paper briefly summarizes the Rhenohercynian and reviews the relicts of the Rheic. The absence of a Rheic orogen is mainly due to bipolar subduction of the Rheic Ocean, which created two magmatic arcs and largely destroyed the passive margin prisms, thus depriving the collision zone of building material. Also, displacement of Variscan zones in England, France and Germany along a curvature of the dextral Bristol/Bray/Bohemia shear zone has effected their anticlockwise rotation. Younger, ENE-trending reverse faults have truncated the NE-trending structural boundaries and excised pre-Devonian, Rheic-related rocks west of the River Rhine, while the northern Rheic Arc and Cambrian–Silurian deposits of the Rheic Ocean have been preserved further east. Opening of the Rhenohercynian successor ocean to the Rheic put a brake on plate convergence and hindered formation of a large collisional belt. Scarce relicts of the southern Rheic Arc and rocks with Silurian deformation exist in the (largely eroded) upper plate of the Rhenohercynian collisional belt, mostly in the form of clasts and detrital zircons in Upper Devonian/lower Carboniferous flysch and in tectonic mélange at the base of the allochthon.
Bilateral Ovarian Serous Borderline Tumor with Non-Invasive Endometrial Implants
Authors: Malham Melissa Bou , Mehawej Jordy , Filippaios Andreas , Kushnir Christina , Mhawech-Fauceglia Paulette 
Published: June 2023

Herein, we are presenting a case of a 33-year-old woman who presented to the emergency department complaining of persistent lower abdominal pain of one-day duration. Physical examination revealed abdominal tenderness with right lower quadrant rebound tenderness. Computed tomography abdomen/pelvis showed a 6 cm possible necrotic mass of the left ovary with moderate amount of complex ascites. A laparoscopic left oophorectomy with bilateral salpingectomy, right ovarian biopsy, and appendectomy were performed without complications. The cut surface of the left ovary showed a

9.7

cm
×
8

cm
×
4

cm

ovarian mass, and the cut surface revealed multiple gray-tan friable papillary excrescence. Microscopic evaluation showed findings consistent with left and right ovarian serous borderline tumor (SBT). Subsequently, a tumor staging was conducted with total laparoscopic hysterectomy, pelvic and periaortic lymph node dissection, and omentectomy. The endometrium sections showed several small foci of SBT within the endometrial stroma, consistent with non-invasive implants of the endometrium. The omentum and lymph nodes were all negative for malignancy. SBTs associated with endometrial implants are very rare with only one case reported in the literature. Their existence can cause diagnostic challenges, and they should be acknowledged for early diagnosis and to plan for patient’s treatment and outcome.
Characterizing Evolutionary Dynamics Reveals Strategies to Exhaust the Spectrum of Subclonal Resistance in EGFR-Mutant Lung Cancer
Authors: Müller Nina , Lorenz Carina , Ostendorp Jenny , Heisel Felix S. , Friese Ulrich P. , Cartolano Maria , Plenker Dennis , Tumbrink Hannah , Heimsoeth Alena , Baedeker Philipp , Weiss Jonathan , Ortiz-Cuaran Sandra , Büttner Reinhard , Peifer Martin , Thomas Roman K. , Sos Martin L. , Berg Johannes , Brägelmann Johannes 
Published: June 2023

Abstract

The emergence of resistance to targeted therapies restrains their efficacy. The development of rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening to systematically extract and define preexisting resistant subpopulations in an EGFR-driven lung cancer cell line. Integrating these modalities identifies several resistance mechanisms, including activation of YAP/TAZ signaling by WWTR1 amplification, and estimates the associated cellular fitness for mathematical population modeling. These observations led to the development of a combination therapy that eradicated resistant clones in large cancer cell line populations by exhausting the spectrum of genomic resistance mechanisms. However, a small fraction of cancer cells was able to enter a reversible nonproliferative state of drug tolerance. This subpopulation exhibited mesenchymal properties, NRF2 target gene expression, and sensitivity to ferroptotic cell death. Exploiting this induced collateral sensitivity by GPX4 inhibition clears drug-tolerant populations and leads to tumor cell eradication. Overall, this experimental in vitro data and theoretical modeling demonstrate why targeted mono- and dual therapies will likely fail in sufficiently large cancer cell populations to limit long-term efficacy. Our approach is not tied to a particular driver mechanism and can be used to systematically assess and ideally exhaust the resistance landscape for different cancer types to rationally design combination therapies.

Significance:
Unraveling the trajectories of preexisting resistant and drug-tolerant persister cells facilitates the rational design of multidrug combination or sequential therapies, presenting an approach to explore for treating EGFR-mutant lung cancer.
Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin–Drug Conjugate Response
Authors: Hu Huiyu , Ng Thomas S.C. , Kang Mikyung , Scott Ella , Li Ran , Quintana Jeremy M. , Matvey Dylan , Vantaku Venkata R. , Weissleder Ralph , Parangi Sareh , Miller Miles A. 
Published: June 2023

Abstract

Purpose:
Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK–ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies.

Experimental Design:
Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53−/− ATC tumors in immunocompetent mice were used to measure efficacy of an albumin–drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE).

Results:
FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by &gt;90% (P &lt; 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri.

Conclusions:
These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
A CAPTIVATEing Analysis for Higher-Risk CLL
Authors: Rogers Kerry A. 
Published: June 2023

Summary
In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin heavy chain variable (IGHV) unmutated status, del(17p), and/or TP53 mutation had similar efficacy and safety outcomes compared with patients without a higher-risk feature when treated with fixed-duration ibrutinib and venetoclax.
See related article by Allan et al., p. 2593
FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements
Authors: Gandhy Shruti U. , Casak Sandra J. , Mushti Sirisha L. , Cheng Joyce , Subramaniam Sriram , Zhao Hong , Zhao Miao , Bi Youwei , Liu Guansheng , Fan Jianghong , Adeniyi Oluseyi , Charlab Rosane , Kufrin Dubravka , Thompson Matthew D. , Jarrell Kristin , Auth Doris , Lemery Steven J. , Pazdur Richard , Kluetz Paul G. , Fashoyin-Aje Lola A. 
Published: June 2023

AbstractOn September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120–101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%–52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.
Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell–Intrinsic Dysfunction
Authors: Jung In-Young , Bartoszek Robert L. , Rech Andrew J. , Collins Sierra M. , Ooi Soon-Keat , Williams Erik F. , Hopkins Caitlin R. , Narayan Vivek , Haas Naomi B. , Frey Noelle V. , Hexner Elizabeth O. , Siegel Donald L. , Plesa Gabriela , Porter David L. , Cantu Adrian , Everett John K. , Guedan Sonia , Berger Shelley L. , Bushman Frederic D. , Herbst Friederike , Fraietta Joseph A. 
Published: June 2023

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon–mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon–associated CAR T cell failure and shorter patient survival. These findings connect prolonged CAR T cell activation with deleterious immunoinflammatory signaling and point to an EGR2–type I interferon axis as a therapeutically amenable biological system.

Significance:
To improve CAR T cell therapy outcomes, modulating molecular determinants of CAR T cell–intrinsic resistance is crucial. Editing the gene encoding the EGR2 transcriptional regulator renders CAR T cells impervious to type I interferon pathway–induced dysfunction and improves memory differentiation, thereby addressing major barriers to progress for this emerging class of cancer immunotherapies.
This article is highlighted in the In This Issue feature, p. 1501
Redox Dysregulation of Vascular Smooth Muscle Sirtuin-1 in Thoracic Aortic Aneurysm in Marfan Syndrome
Authors: Budbazar Enkhjargal , Sulser Ponce De Leon Sandra , Tsukahara Yuko , Liu Hanxiao , Huangfu Yuhao , Wang Yu , Seabra Pedro Maria , Yang Xiaoqiu , Goodman Jena Brooke , Wan Xueping , Chitalia Vipul , Han Jingyan , Seta Francesca 
Published: June 2023

BACKGROUND:
Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases).

METHODS:

In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1
mgR/mgR
), an established model of Marfan syndrome prone to aortic dissection/rupture.

RESULTS:

Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1
mgR/mgR
mice, before induction of severe oxidative stress markers. Fbn1
mgR/mgR
aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFβ (transforming growth factor beta), which was increased in Fbn1
mgR/mgR
aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell–specific deletion of SirT1 in Fbn1
mgR/mgR
mice (SMKO-Fbn1
mgR/mgR
) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1
mgR/mgR
mice, compared with 25% of Fbn1
mgR/mgR
mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells.

CONCLUSIONS:
Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA and TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed.
Single-Pill Combination Product Availability of the Antihypertensive Regimens Used for Intensive Systolic Blood Pressure Treatment in the Systolic Blood Pressure Intervention Trial
Authors: King Jordan B. , Derington Catherine G. , Herrick Jennifer S. , Jacobs Joshua A. , Zheutlin Alexander R. , Conroy Molly B. , Cushman William C. , Bress Adam P. 
Published: June 2023

BACKGROUND:
Single-pill combination (SPC) antihypertensive products improve blood pressure control and medication adherence among patients with hypertension. It is unknown to what degree commercially available SPC products could be used to target an intensive systolic blood pressure goal of <120 mm Hg.

METHODS:
This cross-sectional analysis included participants randomized to the intensive treatment arm (goal systolic blood pressure <120 mm Hg) of the Systolic Blood Pressure Intervention Trial (SPRINT) using ≥2 antihypertensive medication classes at the 12-month postrandomization visit. Antihypertensive medication data were collected using pill bottle review by research coordinators, and regimens were categorized by the unique combinations of antihypertensive classes. We calculated the proportion of regimens used, which are commercially available as one of the 7 SPC class combinations in the United States as of January 2023.

RESULTS:
Among the 3833 SPRINT intensive arm participants included (median age, 67.0 years; 35.5% female), participants were using 219 unique antihypertensive regimens. The 7 regimens for which there are class-equivalent SPC products were used by 40.3% of participants. Only 3.2% of all medication class regimens used are available as a class-equivalent SPC product (7/219). There are no SPC products available with 4 or more medication classes, which were used by 1060 participants (27.7%).

CONCLUSIONS:
Most SPRINT participants in the intensive arm used an antihypertensive medication regimen, which is not commercially available as a class equivalent SPC product. To achieve the SPRINT results in real-world settings, maximize the potential benefit of SPCs, and reduce pill burden, improvements in the product landscape are needed.

REGISTRATION:

URL:
https://www.clinicaltrials.gov/ct2/show/NCT01206062
; Unique identifier: NCT01206062.
The Origins of Mircea Eliade’s Transconscious and the Vicissitudes of the Religious Faculty
Authors: Iagher Matei 
Published: June 2023

Abstract
This article examines the genealogy of the concept of “transconscious,” a key notion in the work of Mircea Eliade. It argues that the “transconscious” is the inheritor of a long psychological tradition in the study of religion, namely that of the religious faculty. The first section looks at the religious faculty in the work of Max Müller and some of his German post-Kantian precursors, namely, Friedrich Jacobi and Jakob Fries. The subsequent sections examine the history of terms such as “super-conscious,” “supra-conscious,” and “trans-conscious” in turn-of-the-century philosophy and theology in the period before 1947. I argue that there are four intellectual strands that go into the making of Eliade’s “transconscious,” namely: (1) psychology of mysticism; (2) occultism; (3) interpretations of yoga; (4) contemporary philosophy and theology. The final section looks at Eliade’s uses of the “transconscious” and at his debate with C. G. Jung regarding religion and the mind.
Governing Health: The Doctor’s Authority, the Patient’s Agency, and the Reading of Regimina sanitatis Literature
Authors: Nicoud Marilyn 
Published: June 2023

Abstract
This article examines the ways in which, in the last centuries of the Middle Ages, the emergence of a literature aimed at preserving health by means of dietary rules or advice establishes a connection between the physician’s authority in matters of health and the capacity of patients and readers to take care of themselves when they are in good health. Born at the same time of social demand and medical necessity (the latter due to the dangers and uncertainties of therapeutic practice), these regimina sanitatis disseminate to a literate public the principles of good hygiene. Some regimina are even adapted to the singularity of a given individual. But the agency of readers, characterized by their capacity for choice and deliberation, also clashes with the claim that a medical authority is necessary for the governance of health.
Astrological Self-Government at the Fifteenth-Century Court of Bourbon
Authors: Vanden Broecke Steven 
Published: June 2023

Abstract
In articulating the uses of their art, late-medieval astrologers often invoked the maxim that “the wise man will rule the stars” (sapiens dominabitur astris). However, it is by no means clear whether this invocation sought to emphasize ‘domination’ over the natural and social world, or the ontological self-government that is at stake in the pursuit of ‘wisdom’. Many historians have interpreted the past pursuit of astrology in terms of an interest in dominance over the natural and social world. Taking inspiration from a recent ‘ascetic turn’ in the history of early modern science and philosophy, however, this article argues that late-medieval astrology was approached and appreciated as an art of self-government (both in body and in soul) and uncovers what this entailed. In so doing, we also demonstrate that the undifferentiated view of astrology as a pre-modern counterpart of modern prospective knowledge practices is anachronistic.
CT values of contrast-enhanced CBBCT: A useful diagnostic tool for benign and malignant breast lesions
Authors: Wei Wei , Yi Xian Lin , Yang Jun , Liao Hai , Su DanKe 
Published: June 2023

Background Computed tomography (CT) value studies of cone-beam breast CT (CBBCT) mainly focus on the enhancement value or enhancement rate, and there has been no study on the CT value (Hounsfield units [HU]) of the lesion itself. Purpose To investigate the CT values under contrast-enhanced CBBCT (CE-CBBCT) and non-contrast-enhanced CBBCT (NC-CBBCT) in scanning for the differential diagnosis of benign and malignant breast lesions. Material and Methods A retrospective analysis was performed on 189 cases of mammary glandular tissues that underwent NC-CBBCT and CE-CBBCT examination. The qualitative CT values of the lesions, standardized Δ(L-A), standardized Δ*(L - G), standardized Δ(L-A) (Post 1st-Pre), and standardized Δ*(L-G) (Post 2nd-Post 1st) between the benign and malignant groups were compared. Prediction performance was evaluated using receiver operating characteristic (ROC) curves. Results In total, 58 cases were included in the benign group, 79 cases were included in the malignant group, and 52 cases were included in the normal group. The best diagnostic thresholds of CT values for L (Post 1st-Pre), Δ(L-A) (Post 1st-Pre), and Δ*(L-G) (Post 1st-Pre) were 49.5, 44, and 64.8 HU, respectively. The Δ(L-A) Post-1st rate values of CBBCT had medium diagnostic efficacy (AUC = 0.74, sensitivity = 76.6%, specificity = 69.4%). Conclusion CE-CBBCT can improve the diagnostic efficiency of breast lesions compared with NC-CBBCT. The CT values (HU) of lesions do not need to be standardized with fat and can be directly used in clinical differential diagnosis. The first contrast phase (60 s) is recommended to reduce the radiation exposure.
Validation of the combined Patient Health Questionnaire Anxiety and Depression Scale among people with HIV in Vietnam
Authors: Nguyen Minh X , Zimmer Catherine , Latkin Carl A , Lancaster Kathryn E , Dowdy David W , Hutton Heidi , Chander Geetanjali , Frangakis Constantine , Gaynes Bradley N , Sripaipan Teerada , Tran Ha V , Go Vivian F 
Published: June 2023

Background Our study aims to examine the factor structure, validity, and reliability of the combined scale Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) among people with HIV (PWH) in Vietnam. Methods Baseline data from an alcohol-reduction intervention trial among ART clients in Thai Nguyen, Vietnam were used for this analysis ( n = 1547). A score ≥10 on the PHQ-9, GAD-7 and PHQ-ADS scale was considered having clinically meaningful depression, anxiety and distress symptoms. Factor structure of the combined PHQ-ADS scale was validated using confirmatory factor analysis, and three models were tested: a one-factor, a two-factor, and a bi-factor model. Reliability and construct validity were examined. Results The prevalence of clinically meaningful depression and anxiety symptoms was 7% and 2%, respectively, while 19% had distress symptoms. A bi-factor model had the best fit to the data (RMSEA = 0.048; CFI = 0.99; TLI = 0.98). The Omega index of the bi-factor model was 0.97. The scale showed good construct validity through negative associations between depression, anxiety, distress symptoms and quality of life. Conclusions Our study supports the use of a combined scale to measure general distress for PWH, which has good validity, reliability and is unidimensional enough to justify the use of a composite depression and anxiety score.