bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of specialised versus generalised outpatient treatment for bipolar disorder: the CAG Bipolar trial - study protocol for a randomised controlled trial
Authors: Kessing Lars Vedel , Kyster Natacha Blauenfeldt , Bondo-Kozuch Pernille , Christensen Ellen Margrethe , Vejstrup Birgitte , Smidt Birte , Jørgensen Anne-Marie Bangsgaard , Rosenberg Raben , Mardosas Darius , Rasmussen Louise Behrend , Vinberg Maj , Hageman Ida , Faurholt-Jepsen Maria 
Published: October 2021

IntroductionDespite current available treatment patients with bipolar disorder often experience relapses and decreased overall functioning. Furthermore, patients with bipolar disorder are often not treated medically or psychologically according to guidelines and recommendations. A Clinical Academic Group is a new treatment initiative bringing together clinical services, research, education and training to offer care and treatment that is based on reliable evidence backed up by research. The present Clinical Academic Group for bipolar disorder (the CAG Bipolar) randomised controlled trial (RCT) aims for the first time to investigate whether specialised outpatient treatment in CAG Bipolar versus generalised community-based treatment improves patient outcomes and clinician’s satisfaction with care in patients with bipolar disorder.Methods and analysisThe CAG Bipolar trial is a pragmatic randomised controlled parallel-group trial undertaken in the Capital Region of Denmark covering a catchment area of 1.85 million people. Patients with bipolar disorder are invited to participate as part of their outpatient treatment in the Mental Health Services. The included patients will be randomised to (1) specialised outpatient treatment in the CAG Bipolar (intervention group) or (2) generalised community-based outpatient treatment (control group). The trial started 13 January 2020 and has currently included more than 600 patients. The outcomes are (1) psychiatric hospitalisations and cumulated number and duration of psychiatric hospitalisations (primary), and (2) self-rated depressive symptoms, self-rated manic symptoms, quality of life, perceived stress, satisfaction with care, use of medication and the clinicians’ satisfaction with their care (secondary). A total of 1000 patients with bipolar disorder will be included.Ethics and disseminationThe CAG Bipolar RCT is funded by the Capital Region of Denmark and ethical approval has been obtained from the Regional Ethical Committee in The Capital Region of Denmark (H-19067248). Results will be published in peer-reviewed academic journals, presented at scientific meetings and disseminated to patient organisations and media outlets.Trial registration numberNCT04229875.
Measurement of breathing in patients with post-COVID-19 using structured light plethysmography (SLP)
Authors: Alhuthail Eyas , Stockley James , Coney Andrew , Cooper Brendan 
Published: October 2021

IntroductionCOVID-19 pandemic has had a huge impact on global health to date, with 5.6 million cases in the UK since its emergence. The respiratory symptoms largely mimic those of pneumonia’ with symptoms ranging from mild to severe. The effects on respiratory physiology are not yet fully understood, but evidence is emerging that there is much dysfunctional breathing reported but little information on tidal ventilation from the acute phase of the infection. Structured light plethysmography (SLP) is a contactless technique of respiratory function testing that measures tidal breathing parameters by assessing thoracoabdominal displacement.MethodsIn a postdischarge clinic, SLP was performed routinely on 110 hospitalised patients recovering from COVID-19 who had been screened for respiratory symptoms to confirm any respiratory changes occurring after the disease. Patients were categorised based on their hospital treatment in (1) the intensive therapy unit (ITU) (requiring intubation) (n=65) or (2) respiratory wards only (n=45). Data from these two patient cohorts were compared with preacquired data from healthy controls (n=30).ResultsWe have found a significantly increased respiratory rate (p=0.006) in ITU patients compared with the healthy cohort and also a significant decrease in the inspiratory time (p=0.01), expiratory time (p=0.005) and the total breathing cycle (p=0.008). There were no significant differences between ITU and ward patients and no significant differences in healthy compared with ward patients. We examined the variability of breathing (‘entropy’) both in terms of the breath-to-breath interval and the volume-to-volume change. The breath-to-breath interval alone was significantly lower in ITU patients compared with healthy cohorts (p=0.02).ConclusionOur findings suggest that abnormalities in tidal breathing can be detected in COVID-19 recovery patients, and SLP may be a promising tool in assessing the aftermath of diseases such as COVID-19, particularly if more intensive management strategies such as mechanical ventilation are required.
Transarterial embolization of dural arteriovenous fistulas of the lateral sinuses with stent-assisted sinus protection
Authors: Guédon Alexis , Elhorany Mahmoud , Labeyrie Marc-Antoine , Civelli Vittorio , Saint-Maurice Jean-Pierre , Houdart Emmanuel 
Published: October 2021

BackgroundThe balloon-assisted sinus protection technique has been described as a sinus-preserving technique during transarterial embolization (TAE) of dural arteriovenous fistulas (DAVFs). However, some serious complications of this technique have been documented.ObjectiveTo describe our preliminary experience with a new technique called stent-assisted sinus protection (SSP).MethodsWe performed a retrospective analysis of seven consecutive patients with type I or IIa DAVFs of the lateral sinus treated by TAE with a closed-cell stent temporarily deployed in the sinus.ResultsOf the seven patients, four had type I DAVF, and three had type IIa DAVF. The patency of all involved sinuses and their tributaries (including the inferior anastomotic vein and the superior petrosal sinus) was preserved. At the end of the procedure, all stents were successfully retrieved with embolic particles trapped in their meshes. No procedural complications were noted. Clinical follow-up was satisfactory, with complete resolution or significant reduction of pulsatile tinnitus.ConclusionsSSP appears to be feasible and probably safe. However, larger studies are needed to confirm these preliminary results.
New static cylindrical symmetric solutions in GR for unfamiliar EoS parameter values via Noether symmetry
Authors: Öz Işıl Başaran , Bamba Kazuharu 
Published: October 2021

AbstractThe solutions for the field equations of f(R) gravity are investigated in static cylindrically symmetric space-time. Conserved quantities of the system, as well as unknown functions, can be determined with the help of the Noether symmetry method. In this article, some unknown values of the equations of state parameter (EoS) have emerged as a result of the constraints obtained by analyzing the Noether symmetry equations for the $$f(R)=f_0 R$$

f

(
R
)

=

f
0

R

case. Consequently, several new exact solutions have been found for cases of General Relativity in static cylindrically symmetrical space-time for the non-dust matter.
Irreducible representations of simple Lie algebras by differential operators
Authors: Morozov A. , Reva M. , Tselousov N. , Zenkevich Y. 
Published: October 2021

AbstractWe describe a systematic method to construct arbitrary highest-weight modules, including arbitrary finite-dimensional representations, for any finite dimensional simple Lie algebra $${\mathfrak {g}}$$
g
. The Lie algebra generators are represented as first order differential operators in $$\frac{1}{2} \left( \dim {\mathfrak {g}} - \text {rank} \, {\mathfrak {g}}\right) $$

1
2

dim
g
-
rank

g

variables. All rising generators $$\mathbf{e}$$
e
are universal in the sense that they do not depend on representation, the weights enter (in a very simple way) only in the expressions for the lowering operators $$\mathbf{f}$$
f
. We present explicit formulas of this kind for the simple root generators of all classical Lie algebras.
Maxwell-modified metric affine gravity
Authors: Cebecioğlu Oktay , Kibaroğlu Salih 
Published: October 2021

AbstractWe present a gauge formulation of the special affine algebra extended to include an antisymmetric tensorial generator belonging to the tensor representation of the special linear group. We then obtain a Maxwell modified metric affine gravity action with a cosmological constant term. We find the field equations of the theory and show that the theory reduces to an Einstein-like equation for metric affine gravity with the source added to the gravity equations with cosmological constant $$\mu $$
μ
contains linear contributions from the new gauge fields. The reduction of the Maxwell metric affine gravity to Riemann–Cartan one is discussed and the shear curvature tensor corresponding to the symmetric part of the special linear connection is identified with the dark energy. Furthermore, the new gauge fields are interpreted as geometrical inflaton vector fields which drive accelerated expansion.
Asymptotic Distributions for Power Variations of the Solution to the Spatially Colored Stochastic Heat Equation
Authors: Wang Wensheng , Chang Xiaoying , Liao Wang 
Published: October 2021

Let

u

α
,
d

=

u

α
,
d

t
,
x

,

t
∈

0
,
T

,
x
∈

ℝ

d

be the solution to the stochastic heat equations (SHEs) with spatially colored noise. We study the realized power variations for the process

u

α
,
d

, in time, having infinite quadratic variation and dimension-dependent Gaussian asymptotic distributions. We use the underlying explicit kernels and spectral/harmonic analysis, yielding temporal central limit theorems for SHEs with spatially colored noise. This work builds on the recent works on delicate analysis of variations of general Gaussian processes and SHEs driven by space-time white noise.
Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate Cancer
Authors: Kumar Rajendra , Mendonca Janet , Owoyemi Olutosin , Boyapati Kavya , Thomas Naiju , Kanacharoen Suthicha , Coffey Max , Topiwala Deven , Gomes Carolina , Ozbek Busra , Jones Tracy , Rosen Marc , Dong Liang , Wiens Sadie , Brennen W. Nathaniel , Isaacs John T. , De Marzo Angelo M. , Markowski Mark C. , Antonarakis Emmanuel S. , Qian David Z. , Pienta Kenneth J. , Pardoll Drew M. , Carducci Michael A. , Denmeade Samuel R. , Kachhap Sushant K. 
Published: October 2021

AbstractThe discovery that androgens play an important role in the progression of prostate cancer led to the development of androgen deprivation therapy (ADT) as a first line of treatment. However, paradoxical growth inhibition has been observed in a subset of prostate cancer upon administration of supraphysiologic levels of testosterone (SupraT), both experimentally and clinically. Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive prostate cancer cells. This was initiated by the induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activated nucleic acid sensors converge on NFκB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT resulted in increased migration of cytotoxic immune cells to tumor beds in xenograft models and patient tumors. Collectively, these findings indicate that SupraT may inhibit a subset of prostate cancer by activating nucleic acid sensors and downstream immune signaling.Significance:This study demonstrates that supraphysiologic testosterone induces two parallel autophagy-mediated processes, ferritinophagy and nucleophagy, which then activate nucleic acid sensors to drive immune signaling pathways in prostate cancer.
Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Tang Donge , Dai Yong , Xu Songhui 
Published: October 2021

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.

Significance:
These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.
ANGPTL4-Mediated Promotion of Glycolysis Facilitates the Colonization ofFusobacterium nucleatumin Colorectal Cancer
Authors: Zheng Xin , Liu Rui , Zhou Chenchen , Yu Haopeng , Luo Wanyi , Zhu Jianhui , Liu Jiaxin , Zhang Zhe , Xie Na , Peng Xian , Xu Xin , Cheng Lei , Yuan Quan , Huang Canhua , Zhou Xuedong 
Published: October 2021

AbstractColorectal cancer is a severe health problem worldwide, and accumulating evidence supports the contribution of Fusobacterium nucleatum (F. nucleatum) to colorectal cancer development, metastasis, and chemoresistance. However, the mechanisms underlying the colonization of F. nucleatum in colorectal cancer tissue are not yet clarified. Here we demonstrate that F. nucleatum infection mediated elevation of angiopoietin-like 4 (ANGPTL4) expression. Upregulated ANGPTL4 promoted glucose uptake and glycolysis activity in colorectal cancer cells in vitro and in vivo, which are necessary for the colonization of F. nucleatum. Furthermore, overall increased acetylation of histone H3 lysine 27 was observed in F. nucleatum–infected colorectal cancer cells and patient tumors, which was responsible for the corresponding transcriptional upregulation of ANGPTL4. These data indicate that the metabolic reprogramming of cancer cells induced by F. nucleatum is essential for its enrichment and persistence in colorectal cancer, providing a novel potential target for the clinical intervention of F. nucleatum–related colorectal cancer.Significance:F. nucleatum colonization in colorectal cancer is regulated by ANGPTL4-mediated glycolysis, suggesting that this axis could be targeted for combined repression of F. nucleatum and cancer progression.
Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study
Authors: Moore Kathleen N. , Chambers Setsuko K. , Hamilton Erika P. , Chen Lee-may , Oza Amit M. , Ghamande Sharad A. , Konecny Gottfried E. , Plaxe Steven C. , Spitz Daniel L. , Geenen Jill J.J. , Troso-Sandoval Tiffany A. , Cragun Janiel M. , Rodrigo Imedio Esteban , Kumar Sanjeev , Mugundu Ganesh M. , Lai Zhongwu , Chmielecki Juliann , Jones Suzanne F. , Spigel David R. , Cadoo Karen A. 
Published: October 2021

Abstract

Purpose:
This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer.

Patients and Methods:
Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate.

Results:
Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each].

Conclusions:
Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2− Breast Cancer
Authors: Dowsett Mitch , Kilburn Lucy , Rimawi Mothaffar F. , Osborne C. Kent , Pogue-Geile Katherine , Liu Yuan , Jacobs Samuel A. , Finnigan Melanie , Puhalla Shannon , Dodson Andrew , Martins Vera , Cheang Maggie , Perry Sophie , Holcombe Chris , Turner Nick , Swift Claire , Bliss Judith M. , Johnston Stephen ,   on behalf of the PALLET trialists
Published: October 2021

Abstract

Purpose:
To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2− breast cancer; and (ii) the pharmacodynamic effect of the agents on the biomarkers.

Experimental Design:
307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1.

Results:
Higher baselines ER and PgR were significantly associated with a greater chance of complete cell-cycle arrest (CCCA: Ki67 &lt;2.7%) at 14 weeks and higher baseline Ki67, c-PARP, and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumors showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumors showed CCCA 3–9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumors for which surgery took place ≥6 months after starting treatment.

Conclusions:
High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3–9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the “off” week of its schedule.
Phase Ib/II Study of Cetuximab plus Pembrolizumab in Patients with Advanced RAS Wild-Type Colorectal Cancer
Authors: Fountzilas Christos , Bajor David L. , Mukherjee Sarbajit , Saltzman Joel , Witkiewicz Agnieszka K. , Maguire Orla , Minderman Hans , Nambiar Ram , Rosenheck Hanna R. , Knudsen Erik S. , Muhitch Jason B. , Abrams Scott I. , Wang Chong , Hutson Alan D. , Attwood Kristopher , Hicks Karen A. , Jurcevic Jennifer A. , Kalinski Pawel , Iyer Renuka , Boland Patrick M. 
Published: October 2021

Abstract

Purpose:
We evaluated the antitumor efficacy of cetuximab in combination with pembrolizumab in patients with RAS wild-type (RASwt), metastatic colorectal adenocarcinoma (mCRC).

Patients and Methods:
In this phase Ib/II study, cetuximab was combined with pembrolizumab in patients with RASwt mCRC with ≥ one prior line of therapy for advanced disease. We analyzed baseline on-treatment tumor tissues for changes in the tumor microenvironment (TME), using flow cytometry and multispectral immunofluorescence.

Results:
Forty-four patients were evaluable for efficacy. The study was negative for the primary efficacy endpoint [overall response rate: 2.6%, 6-month progression-free survival (PFS): 31%; P = 0.52]. Median PFS was 4.1 months [95% confidence interval (CI): 3.9–5.5 months]. No increase in adverse effects was identified. We observed favorable immunomodulation with 47% increase in the number of intratumoral CTLs posttreatment (P = 0.035). These changes were more pronounced in patients with tumor shrinkage (P = 0.05). The TME was characterized by high numbers of TIM3+ and CTLA4+ cells; there were few activated OX40+ cells. PD-L1 expression was higher in pretreatment tumor cells from metastatic sites versus primary tumor samples (P &lt; 0.05). Higher numbers of PD-L1+ tumor cells at baseline were associated with tumor shrinkage (P = 0.04). Analysis of immune populations in the blood demonstrated decreases in PD-1+ memory effector cells (P = 0.04) and granulocytic myeloid-derived suppressor cells (P = 0.03), with simultaneous increases in CD4+/CTLA4+ cells (P = 0.01).

Conclusions:
The combination of cetuximab and pembrolizumab is inactive in patients with RASwt mCRC, despite its partial local immunologic efficacy. Further development of immuno-oncology combinations with enhanced efficacy and/or targeting additional or alternative immune checkpoints merits investigation.