bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed/refractory Hodgkin lymphoma
Authors: Liu Yang , Wang Chunmeng , Li Xiang , Dong Liang , Yang Qingming , Chen Meixia , Shi Fengxia , Brock Malcolm , Liu Miao , Mei Qian , Liu Jiejie , Nie Jing , Han Weidong 
Published: April 2021

BackgroundProgrammed death-1 (PD-1) blockade monotherapy induced durable remission in a subset of patients with relapsed/refractory classical Hodgkin lymphoma (cHL). We asked whether the anti-PD-1 agent, camrelizumab, combined with the DNA demethylating agent, decitabine, improves progression-free survival (PFS) in patients with relapsed/refractory cHL over camrelizumab alone.MethodsThis extended follow-up of an ongoing randomized phase II trial analyzed PFS among patients enrolled from January 2017 through July 2018. Sixty-one patients with relapsed/refractory cHL who were clinically naïve to PD-1 blockade and had received ≥2 previous therapies were randomized 1:2 to receive either camrelizumab (200 mg) monotherapy or camrelizumab (200 mg, day 8) combined with decitabine (10 mg/day, days 1–5) every 3 weeks.ResultsWith a median follow-up of 34.5 months, complete remission was 79% (95% CI 63% to 90%) in the decitabine-plus-camrelizumab group versus 32% (95% CI 13% to 57%) in the camrelizumab group (p=0.001). Median duration of response was not reached in the decitabine-plus-camrelizumab group, with an estimated 63% (95% CI 46% to 75%) of patients maintaining a response at 24 months. Median PFS with decitabine-plus-camrelizumab therapy was 35.0 months (95% CI not reached) and 15.5 months (95% CI 8.4 to 22.7 months) with camrelizumab monotherapy (HR, 0.46; 95% CI 0.21 to 1.01; p=0.02). Female gender, lower tumor burden, and fewer previous therapies were favorable prognostic factors for durable remission with camrelizumab monotherapy. The PFS benefits of decitabine-plus-camrelizumab versus camrelizumab were observed in most subgroups, especially in patients with relative larger tumor burdens and those treated with ≥3 prior therapies. After decitabine-plus-camrelizumab treatment, the percentage increase of circulating peripheral central memory T-cells correlated with both improved clinical response and PFS, suggesting a putative biomarker of decitabine-plus-camrelizumab therapy for cHL.ConclusionsDecitabine-plus-camrelizumab results in longer PFS compared with camrelizumab alone in patients with relapsed/refractory cHL.Trial registration numbersNCT02961101andNCT03250962.
Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly
Authors: Drissi Ichrak , Fletcher Emily , Shaheen Ranad , Nahorski Michael , Alhashem Amal M , Lisgo Steve , Fernández-Jaén Alberto , Schon Katherine , Tlili-Graiess Kalthoum , Smithson Sarah F , Lindsay Susan , J Sharpe Hayley , Alkuraya Fowzan S , Woods Geoff 
Published: April 2021

BackgroundHoloprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities.MethodsWe describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy.ResultsIn the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygousPLCH1c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygousPLCH1c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant.ConclusionOur data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.
Mid-term outcome of children with latent rheumatic heart disease in eastern Nepal
Authors: Shrestha Nikesh Raj , Bruelisauer Dorothea , Uranw Surendra , Mahato Rajan , Sherpa Kunjang , Agrawal Krishna , Rothenbühler Martina , Karki Prahlad , Pilgrim Thomas 
Published: April 2021

IntroductionSystematic echocardiographic screening of children in regions with an endemic pattern of rheumatic heart disease allows for the early detection of valvular lesions suggestive of subclinical rheumatic heart disease. The natural course of latent rheumatic heart disease is, however, incompletely understood at this time.MethodsWe performed a prospective cohort study of children detected to have echocardiographic evidence of definite or borderline rheumatic heart disease according to the World Heart Federation Criteria.ResultsAmong 53 children found to have definite (36) or borderline (17) rheumatic heart disease, 44 (83%) children underwent follow-up at a median of 1.9 years (IQR 1.1–4.5). The median age of the children was 11 years (IQR 9–14) and 34 (64.2%) were girls. Among children with definite rheumatic heart disease, 21 (58.3%) were adherent to secondary antibiotic prophylaxis, 7 (19.4%) were not, information on adherence was missing in 2 (5.6%) children and 6 (16.7%) were lost to follow-up. Regression of disease was observed in 10 children (27.8%), whereas 20 children (55.6%) had stable disease. Among children adherent to secondary prophylaxis, seven (33.3%) showed regression of disease. Among children with borderline disease, seven (41.2%) showed regression of disease, three (17.6%) progression of disease, four (23.5%) remained stable and three (17.6%) were lost to follow-up. On univariate analysis, we identified no predictors of disease regression, and no predictors for lost to follow-up or non-adherence with secondary antibiotic prophylaxis.ConclusionDefinite rheumatic heart disease showed regression in one in four children. Borderline disease was spontaneously reversible in less than half of the children and progressed to definite rheumatic heart disease in one in five children.Trial registration numberNCT01550068.
The transverse polarization of $$\Lambda $$ hyperons in $$e^+e^-\rightarrow \Lambda ^\uparrow h X$$ processes within TMD factorization
Authors: Li Hui , Wang Xiaoyu , Yang Yongliang , Lu Zhun 
Published: April 2021

AbstractWe investigate the transverse polarization of the $$\Lambda $$
Λ
hyperon in the processes $$e^+e^-\rightarrow \Lambda ^\uparrow \pi ^\pm X$$

e
+

e
-

→

Λ
↑

π
±

X

and $$e^+e^-\rightarrow \Lambda ^\uparrow K^\pm X$$

e
+

e
-

→

Λ
↑

K
±

X

within the framework of the transverse momentum dependent (TMD) factorization. The transverse polarization is contributed by the convolution of the transversely polarizing fragmentation function (PFF) $$D_{1T}^\perp $$

D

1
T

⊥

of the lambda hyperon and the unpolarized fragmentation function $$D_1$$

D
1

of pion/kaon. We adopt the spectator diquark model result for $$D_{1T}^{\perp }$$

D

1
T

⊥

to numerically estimate the transverse polarization in $$e^+e^-\rightarrow \Lambda ^\uparrow h X$$

e
+

e
-

→

Λ
↑

h
X

process at the kinematical region of Belle Collaboration. To implement the TMD evolution formalism of the fragmentation functions, we apply two different parametrizations on the nonperturbative Sudakov form factors associated with the fragmentation functions of the $$\Lambda $$
Λ
, pion and kaon. It is found that our prediction on the polarization in the $$\Lambda \pi ^+$$

Λ

π
+

production and $${\bar{\Lambda }} \pi ^-$$

Λ

¯

π
-

is consistent with the recent Belle measurement in size and sign, while the model predictions on the polarizations in $$\Lambda \pi ^-$$

Λ

π
-

and $$\Lambda K^\pm $$

Λ

K
±

productions show strong disagreement with the Belle data. The reason for the discrepancies is discussed and possible approaches to improve the calculation in the future are also discussed.
Effect of Moxibustion on β-EP and Dyn Levels of Pain-Related Indicators in Patients with Rheumatoid Arthritis
Authors: Wang Yingni , Tao Siyu , Yu Zeyun , Luo Yun , Li Yuan , Tang Jie , Chen Guanhua , Shuai Rouxian , Hu Xinyue , Wu Ping 
Published: April 2021

Background. Rheumatoid arthritis (RA) is a systemic immunodeficiency disease characterized by persistent synovial inflammation, pannus formation, and bone and cartilage destruction, resulting in joint malformations and function decline. Objective. The purpose of this study is to evaluate the effect of moxibustion on clinical symptoms and levels of pain-related indicators beta-endorphin (β-EP) and dynorphin (Dyn) in patients with RA and to explore the potential anti-inflammatory and analgesic mechanisms of moxibustion in RA treatment. Methods. A total of 64 patients with RA who met the inclusion criteria were randomly and equally classified into the control and treatment groups. The control group received conventional treatment (oral methotrexate, folate, or leflunomide prescribed for a long time). The treatment group was treated with moxibustion at ST36 (Zusanli), BL23 (Shenshu), and Ashi points with respect to the control group. Patients’ clinical symptoms and routine inspection indexes (rheumatoid factor [RF], erythrocyte sedimentation rate [ESR], and C-reactive protein [CRP]) were recorded before and after treatment. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), β-EP, and Dyn were determined by enzyme-linked immunosorbent assay (ELISA). The software SPSS24.0 was used for statistical analysis. Results. (1) Compared with the pretreatment result, both of the two groups’ clinical symptoms and routine inspection indexes (RF, ESR, and CRP) improved (

P

< 0.05), and the improvement of clinical symptoms in the treatment group outperformed that in the control group (

P

< 0.05). (2) TNF-α and IL-1β levels decreased significantly in the treatment group after treatment (

P

< 0.01), while no significant difference was observed in the control group (

P

> 0.05). (3) β-EP and Dyn levels in the treatment group were significantly increased after treatment (

P

< 0.01,

P

< 0.01), but the control group showed no significant difference (

P

> 0.05,

P

> 0.05). It is worth mentioning that the serum TNF-α, IL-1β, β-EP, and Dyn levels between the two groups were significantly different after 8 weeks of treatment (

P

< 0.05). (4) Differences in the serum β-EP and Dyn levels in the patients of the treatment group were correlated with TNF-α and IL-1β levels after treatment, and the correlation was mainly negative (r < 0). Conclusion. Moxibustion can improve joint pain in patients with RA using conventional western medicine. One of the mechanisms may affect the serum β-EP and Dyn levels by downregulating the inflammatory factors to play an anti-inflammatory and analgesic role.
Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells
Authors: Alvarez-Trotta Annamil , Guerrant William , Astudillo Luisana , Lahiry Mohini , Diluvio Giulia , Shersher Elena , Kaneku Hugo , Robbins David J. , Orton Darren , Capobianco Anthony J. 
Published: April 2021

AbstractIn many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells (CSC), which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway–specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here, we report the discovery of NADI-351, the first specific small-molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust antitumor activity without inducing intestinal toxicity in mouse models, and CSCs were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment.Significance:This study showcases the first Notch1-selective inhibitor that suppresses tumor growth with limited toxicity by selectively ablating cancer stem cells.
Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy
Authors: Chen Gregory M. , Chen Changya , Das Rajat K. , Gao Peng , Chen Chia-Hui , Bandyopadhyay Shovik , Ding Yang-Yang , Uzun Yasin , Yu Wenbao , Zhu Qin , Myers Regina M. , Grupp Stephan A. , Barrett David M. , Tan Kai 
Published: April 2021

Abstract

The adoptive transfer of chimeric antigen receptor (CAR) T cells represents a breakthrough in clinical oncology, yet both between- and within-patient differences in autologously derived T cells are a major contributor to therapy failure. To interrogate the molecular determinants of clinical CAR T-cell persistence, we extensively characterized the premanufacture T cells of 71 patients with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy. We performed RNA-sequencing analysis on sorted T-cell subsets from all 71 patients, followed by paired Cellular Indexing of Transcriptomes and Epitopes (CITE) sequencing and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on T cells from six of these patients. We found that chronic IFN signaling regulated by IRF7 was associated with poor CAR T-cell persistence across T-cell subsets, and that the TCF7 regulon not only associates with the favorable naïve T-cell state, but is maintained in effector T cells among patients with long-term CAR T-cell persistence. These findings provide key insights into the underlying molecular determinants of clinical CAR T-cell function.

Significance:
To improve clinical outcomes for CAR T-cell therapy, there is a need to understand the molecular determinants of CAR T-cell persistence. These data represent the largest clinically annotated molecular atlas in CAR T-cell therapy to date, and significantly advance our understanding of the mechanisms underlying therapeutic efficacy.
This article is highlighted in the In This Issue feature, p. 2113
Regulatory T-cell Transcriptomic Reprogramming Characterizes Adverse Events by Checkpoint Inhibitors in Solid Tumors
Authors: Grigoriou Maria , Banos Aggelos , Hatzioannou Aikaterini , Kloetgen Andreas , Kouzis Panagiotis , Aggouraki Despoina , Zakopoulou Roubini , Bamias Giorgos , Kassi Eva , Mavroudis Dimitrios , Bamias Aristotelis , Boumpas Dimitrios T. , Tsirigos Aristotelis , Gogas Helen , Alissafi Themis , Verginis Panayotis 
Published: April 2021

Abstract
Immune checkpoint inhibitors (ICI), which target immune regulatory pathways to unleash antitumor responses, have revolutionized cancer immunotherapy. Despite the remarkable success of ICI immunotherapy, a significant proportion of patients whose tumors respond to these treatments develop immune-related adverse events (irAE) resembling autoimmune diseases. Although the clinical spectrum of irAEs is well characterized, their successful management remains empiric. This is in part because the pathogenic mechanisms involved in the breakdown of peripheral tolerance and induction of irAEs remain elusive. Herein, we focused on regulatory T cells (Treg) in individuals with irAEs because these cells are vital for maintenance of peripheral tolerance, appear expanded in the peripheral blood of individuals with cancer, and abundantly express checkpoint molecules, hence representing direct targets of ICI immunotherapy. Our data demonstrate an intense transcriptomic reprogramming of CD4+CD25+CD127− Tregs in the blood of individuals with advanced metastatic melanoma who develop irAEs following ICI immunotherapy, with a characteristic inflammatory, apoptotic, and metabolic signature. This inflammatory signature was shared by Tregs from individuals with different types of cancer developing irAEs and individuals with autoimmune diseases. Our findings suggest that inflammatory Treg reprogramming is a feature of immunotherapy-induced irAEs, and this may facilitate translational approaches aiming to induce robust antitumor immunity without disturbing peripheral tolerance.
Benefits and Harms of Hypertension and High-Normal Labels: A Randomized Experiment
Authors: Muscat Danielle Marie , Morris Georgina May , Bell Katy , Cvejic Erin , Smith Jenna , Jansen Jesse , Thomas Rae , Bonner Carissa , Doust Jenny , McCaffery Kirsten 
Published: April 2021

Background:
Recent US guidelines lowered the threshold for diagnosing hypertension while other international guidelines use alternative/no labels for the same group (blood pressure [BP], <140/90 mm Hg). We investigated potential benefits and harms of hypertension and high-normal BP labels, compared with control, among people at lower risk of cardiovascular disease.

Methods:
We conducted a randomized experiment using a national sample of Australians (n=1318) 40 to 50 years of age recruited from an online panel. Participants were randomized to 1 of 3 hypothetical scenarios where a general practitioner told them they had a BP reading of 135/85 mm Hg, using either hypertension/high-normal BP/control (general BP description) labels. Participants were then randomized to receive an additional absolute risk description or nothing. Primary outcomes were willingness to change diet and worry. Secondary outcomes included exercise/medication intentions, risk perceptions, and other psychosocial outcomes.

Results:

There was no difference in willingness to change diet across label groups (
P
=0.22). The hypertension label (mean difference [MD], 0.74 [95% CI, 0.41–1.06];
P
<0.001) and high-normal BP label (MD, 0.45 [95% CI, 0.12–0.78];
P
=0.008) had increased worry about cardiovascular disease risk compared with control. There was no evidence that either label increased willingness to exercise (
P
=0.80). However, the hypertension (MD, 0.20 [95% CI, 0.04–0.36];
P
=0.014), but not high-normal label (MD, 0.06 [95% CI, −0.10 to 0.21];
P
=0.49), increased willingness to accept BP-lowering medication compared with control. Psychosocial differences including lower control, higher risk perceptions, and more negative affect were found for the hypertension and high-normal labels compared with control. Providing absolute risk information decreased willingness to change diet (MD, 0.25 [95% CI, 0.10–0.41];
P
=0.001) and increase exercise (MD, 0.28 [95% CI, 0.11–0.45];
P
=0.001) in the hypertension group.

Conclusions:
Neither hypertension nor high-normal labels motivated participants to change their diet or exercise more than control, but both labels had adverse psychosocial outcomes. Labeling people with systolic BP of 130 to 140 mm Hg, who are otherwise at low risk of cardiovascular disease, may cause harms that outweigh benefit.

Registration:

URL:
http://www.anzctr.org.au/
; Unique identifier: ACTRN12618001700224.
Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease:
Authors: Doumouras Aristithes G. , Wong Jorge A. , Paterson J. Michael , Lee Yung , Sivapathasundaram Branavan , Tarride Jean-Eric , Thabane Lehana , Hong Dennis , Yusuf Salim , Anvari Mehran 
Published: April 2021

Background:
Bariatric surgery has been shown to significantly reduce cardiovascular risk factors. However, whether surgery can reduce major adverse cardiovascular events (MACE), especially in patients with established cardiovascular disease, remains poorly understood. The present study aims to determine the association between bariatric surgery and MACE among patients with cardiovascular disease and severe obesity.

Methods:
This was a propensity score–matched cohort study using province-wide multiple-linked administrative databases in Ontario, Canada. Patients with previous ischemic heart disease or heart failure who received bariatric surgery were matched on age, sex, heart failure history, and a propensity score to similar controls from a primary care medical record database in a 1:1 ratio. The primary outcome was the incidence of extended MACE (first occurrence of all-cause mortality, myocardial infarction, coronary revascularization, cerebrovascular events, and heart failure hospitalization). Secondary outcome included 3-component MACE (myocardial infarction, ischemic stroke, and all-cause mortality). Outcomes were evaluated through a combination of matching via propensity score and subsequent multivariable adjustment.

Results:

A total of 2638 patients (n=1319 in each group) were included, with a median follow-up time of 4.6 years. The primary outcome occurred in 11.5% (151/1319) of the surgery group and 19.6% (259/1319) of the controls (adjusted hazard ratio [HR], 0.58 [95% CI, 0.48–0.71];
P
<0.001). The association was notable for those with heart failure (HR, 0.44 [95% CI, 0.31–0.62];
P
<0.001; absolute risk difference, 19.3% [95% CI, 12.0%–26.7%]) and in those with ischemic heart disease (HR, 0.60 [95% CI, 0.48–0.74];
P
<0.001; absolute risk difference, 7.5% [95% CI, 4.7%–10.5%]). Surgery was also associated with a lower incidence of the secondary outcome (HR, 0.66 [95% CI, 0.52–0.84];
P
=0.001) and cardiovascular mortality (HR, 0.35 [95% CI, 0.15–0.80];
P
=0.001).

Conclusions:
Bariatric surgery was associated with a lower incidence of MACE in patients with cardiovascular disease and obesity. These findings require confirmation by a large-scale randomized trial.