bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomised clinical trials
Authors: Canoy Dexter , Copland Emma , Nazarzadeh Milad , Ramakrishnan Rema , Pinho-Gomes Ana-Catarina , Salam Abdul , Dwyer Jamie P , Farzadfar Farshad , Sundström Johan , Woodward Mark , Davis Barry R , Rahimi Kazem 
Published: January 2022

ObjectiveEvidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics.MethodsWe conducted an individual patient-level data meta-analysis of 52 large-scale randomised clinical trials in the Blood Pressure Lowering Treatment Trialists’ Collaboration using mixed models to examine treatment effects on BP over 4 years of mean follow-up.ResultsThere were 363 684 participants (42% women), with baseline mean age=65 years and mean systolic/diastolic BP=152/87 mm Hg, and among whom 19% were current smokers, 49% had cardiovascular disease, 28% had diabetes and 69% were taking antihypertensive treatment at baseline. Drugs were effective in lowering BP showing maximal effect after 12 months and gradually attenuating towards later years. Based on measures taken ≥12 months postrandomisation, mean systolic/diastolic BP difference (95% CI) between more and less intense BP-lowering treatment was −11.1 (−11.3 to −10.8)/−5.6 (−5.7 to −5.4) mm Hg; between active treatment and placebo was −5.1 (−5.3 to −5.0)/−2.3 (−2.4 to −2.2) mm Hg; and between active and control arms for drug comparison trials was −1.4 (−1.5 to −1.3)/−0.6 (−0.7 to −0.6) mm Hg. BP reductions were observed across different baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes and prior antihypertensive treatment use.ConclusionThese findings suggest that BP-lowering pharmacotherapy is effective in lowering BP, up to 4 years on average, in people with different characteristics. Appropriate treatment strategies are needed to sustain substantive long-term BP reductions.
Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate
Authors: Merchant Rosemina , Galligan Carole , Munegowda Manjunatha Ankathatti , Pearce L Bruce , Lloyd Peter , Smith Paul , Merchant Fahar , To Minh D 
Published: January 2022

BackgroundRecombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing.MethodsMDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP).ResultsBinding studies with MDNA11 demonstrated increased affinity for IL-2Rβ (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome.ConclusionMDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.
Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors
Authors: Semmrich Monika , Marchand Jean-Baptiste , Fend Laetitia , Rehn Matilda , Remy Christelle , Holmkvist Petra , Silvestre Nathalie , Svensson Carolin , Kleinpeter Patricia , Deforges Jules , Junghus Fred , Cleary Kirstie L , Bodén Mimoza , Mårtensson Linda , Foloppe Johann , Teige Ingrid , Quéméneur Eric , Frendéus Björn 
Published: January 2022

BackgroundImmune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated ‘cold’ tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved αCTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for αCTLA-4; ICB and regulatory T cell (Treg) depletion are both thought to contribute efficacy and toxicity in available, systemic, αCTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe αCTLA-4 therapies have been lacking. Here we assess and identify spatially restricted exposure to a novel strongly Treg-depleting, checkpoint-blocking, vectorized αCTLA-4, as a highly efficacious and potentially safe strategy to target CTLA-4.MethodsA novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for monoclonal antibodies (mAbs) and targets associated with superior Treg-depleting activity. A tumor-selective oncolytic vaccinia vector was then engineered to encode this novel, strongly Treg-depleting, checkpoint-blocking, αCTLA-4 antibody or a matching surrogate antibody, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (VVGM-αCTLA-4).ResultsThe identified 4-E03 antibody showed significantly stronger Treg depletion, but equipotent checkpoint blockade, compared with clinically validated αCTLA-4 ipilimumab against CTLA-4-expressing Treg cells in a humanized mouse model in vivo. Intratumoral administration of VVGM-αCTLA-4 achieved tumor-restricted CTLA-4 receptor saturation and Treg depletion, which elicited antigen cross-presentation and stronger systemic expansion of tumor-specific CD8+ T cells and antitumor immunity compared with systemic αCTLA-4 antibody therapy. Efficacy correlated with FcγR-mediated intratumoral Treg depletion. Remarkably, in a clinically relevant mouse model resistant to systemic ICB, intratumoral VVGM-αCTLA-4 synergized with αPD-1 to reject cold tumors.ConclusionOur findings demonstrate in vivo proof of concept for spatial restriction of Treg depletion-optimized immune checkpoint blocking, vectorized αCTLA-4 as a highly effective and safe strategy to target CTLA-4. A clinical trial evaluating intratumoral VVGM-αhCTLA-4 (BT-001) alone and in combination with αPD-1 in metastatic or advanced solid tumors has commenced.
Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders
Authors: Zhou Liye , Zeng Zexian , Egloff Ann Marie , Zhang Fan , Guo Fei , Campbell Katie M , Du Peter , Fu Jingxin , Zolkind Paul , Ma Xiaojing , Zhang Zhe , Zhang Yi , Wang Xiaoqing , Gu Shengqing , Riley Rachel , Nakahori Yasutaka , Keegan Joshua , Haddad Robert , Schoenfeld Jonathan D , Griffith Obi , Manguso Robert T , Lederer James A , Liu X Shirley , Uppaluri Ravindra 
Published: January 2022

BackgroundImmune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%–20% of patients and underpinnings of resistance remain undefined.MethodsStarting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models.ResultsAnti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1− (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions.ConclusionsThese data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response.
Wisdom of Freezing All Valuable Embryos
Authors: Tanaka Atsushi , Nagayoshi Motoi , Yanagihara Yasuho , Tanaka Izumi , Akahoshi Takako , Araki Megumi , Urabe Nao , Tanaka Akihiro , Sato Tatsuya 
Published: January 2022

Background: It is controversial whether that “Freeze-only” strategy is superior to Fresh embryo transfer in ART patients with normal ovarian response. There are two reasons supporting a “Freeze-only” strategy. One is that frozen-thawed embryos are transferred to a more physiologically receptive endometrium. While fresh embryos are transferred to a badly affected one because of controlled-ovarian stimulations, which cause the discordant development of the endometrium, when thawed-frozen embryos are transferred in a subsequent cycle the endometrium is not affected by high estrogen levels. The other reason is the big difference in cryopreservation and stimulation techniques. Methods: We investigated the annual ART reports in Japan from 1992 to 2018, and our clinical outcomes of frozen-thawed embryo transfers and fresh embryo transfers from 2015 to 2019. This enabled the assessment of the survival rate of frozen blastocyst by Cryotop safety kit after thawing in four different clinics. We compared the outcomes of frozen embryo transfer (FroET) to fresh embryo transfer. Results: The proportion of birth in Japan in the study interval found that FroET was responsible for 86.7% of births, compared to 13.3% of births resulting from fresh embryo transfers after IVF or intracytoplasmic sperm injection (ICSI). Clinical outcome of FroET in our clinic was significantly higher than that of fresh embryo transfer regardless of maternal age and number of collected oocytes. Average survival rate of frozen blastocyst by Cryotop safety kit after thawing in four clinics was over 95%. Conclusions: We believe that “Freeze-only high-quality blastocysts” is superior to fresh embryo transfer in terms of clinical outcome, at least when compared to historical results.
(+)-JJ-74–138 is a Novel Noncompetitive Androgen Receptor Antagonist
Authors: Cole Ryan N. , Chen Wei , Pascal Laura E. , Nelson Joel B. , Wipf Peter , Wang Zhou 
Published: January 2022

AbstractIdentification of novel androgen receptor (AR) antagonists may lead to urgently needed new treatments for patients with prostate cancer resistant to current AR antagonists. AR is presently the main target for treating prostate cancer. Clinically approved AR antagonists compete with dihydrotestosterone (DHT) for binding to the ligand-binding domain (LBD) of AR, and patients eventually develop resistance to these treatments. One approach to overcoming resistance is to discover compounds that inhibit AR in alternative ways. Our lab previously identified a small molecule, JJ-450, that is capable of inhibiting AR lacking LBD. To optimize the efficacy of this class of inhibitors, we developed structural analogues of JJ-450 and identified (+)-JJ-74–138 as a promising candidate. Here, we show that (+)-JJ-74–138 is more potent than JJ-450 in the inhibition of androgen-independent AR activity in enzalutamide-resistant LN95 cells. Further studies showed (+)-JJ-74–138 inhibition of castration-resistant PSA expression in all tested castration-resistant prostate cancer (CRPC) cells. (+)-JJ-74–138 inhibited mRNA expression of AR and ARv7 target genes and reduced AR level in the nucleus in the absence of androgens. Also, this analogue noncompetitively inhibited androgen-stimulated AR activity in C4–2, LN95, and 22Rv1 CRPC cells. At low dosages, (+)-JJ-74–138 inhibited the proliferation of enzalutamide-resistant AR-positive LN95 and 22Rv1 cells, but not AR-negative PC3 and DU145 cells. A surface plasmon resonance assay detected (+)-JJ-74–138 binding to AR and a chromatin immunoprecipitation assay indicated (+)-JJ-74–138 inhibited AR binding to androgen response elements. In addition, (+)-JJ-74–138 inhibited 22Rv1 xenograft tumor growth. Our observations suggest that (+)-JJ-74–138 is a novel noncompetitive AR antagonist capable of inhibiting enzalutamide-resistant CRPC.
Association of PD-L1 Expression on Tumor and Immune Cells with Survival in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma and Assay Validation
Authors: Wildsmith Sophie , Ye Jiabu , Franks April , Melillo Giovanni , Armstrong Jon , Whiteley Jessica , Schnittker Karina , Lian Fangru , Roland Bryan , Sabalos Constantine , Ahmadi Payam , Fayette Jerome , Even Caroline , Mesía Ricard , Siu Lillian L. , Zandberg Dan P. , Walker Jill 
Published: January 2022

Programmed cell death ligand-1 (PD-L1), expressed on both tumor cells (TC) and tumor-associated immune cells (IC), has been shown to be a useful biomarker and predictive of response to anti-PD-L1 agents in certain tumor types. In recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), there is a growing interest in the role of PD-L1 expression on ICs, as well as TCs, for predicting response to immune checkpoint inhibitors. Using pooled data from the phase II HAWK and CONDOR studies, we investigated the association of baseline PD-L1 expression with durvalumab efficacy in patients with R/M HNSCC. To determine an optimal PD-L1 cut-off point for predicting survival, we assessed PD-L1 expression levels at different TC and IC cut-off points in patients treated with durvalumab. Longer survival was associated with higher TC membrane PD-L1 expression and IC staining. When the combined TC/IC algorithm was applied, a cut-off point for PD-L1 expression of ≥50% on TCs or ≥25% on ICs (TC ≥ 50%/IC ≥ 25%) showed a higher objective response rate (17.2% vs. 8.8%), longer median progression-free survival (2.8 vs. 1.9 months), and longer median overall survival (8.4 vs. 5.4 months) in the PD-L1–high versus PD-L1–low/negative patient populations, respectively. A scoring algorithm combining PD-L1 expression on TCs and ICs using the cut-off point TC ≥ 50%/IC ≥ 25% was optimal for identifying patients with HNSCC most likely to benefit from durvalumab treatment. The new algorithm is robust and can be reproducibly scored by trained pathologists.

Significance:
A novel algorithm for PD-L1 expression using the cut-off point TC ≥ 50%/IC ≥ 25% is robust for identifying patients with HNSCC most likely to benefit from durvalumab treatment and can be reproducibly scored by trained pathologists.
DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment
Authors: Wilson Jessica R. , Garner Erica M. , Mashayekhi Mona , Hubers Scott A. , Ramirez Bustamante Claudia E. , Kerman Scott Jafarian , Nian Hui , Shibao Cyndya A. , Brown Nancy J. 
Published: January 2022

Background:
DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study.

Methods:
We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout.

Results:
We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan.

Conclusions:
Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.
Joint Effect of West Pacific Warming and the Arctic Oscillation on the Bidecadal Variation and Trend of the East Asian Trough
Authors: Leung Marco Y.-T. , Wang Dongxiao , Zhou Wen , Cheung Paxson K. Y. , Jian Yuntao , Xiao Fuan 
Published: January 2022

AbstractThis study investigates bidecadal variation and trends in the winter East Asian trough (EAT) intensity for the period from 1958 to 2020. The EAT intensity index, calculated with the JRA55 reanalysis, demonstrates bidecadal variation, which is closely related to the intensity of cold advection in East Asia that affects northeast China, the Korean Peninsula, and Japan. In addition, it is noted that the positive phase of the Arctic Oscillation (AO) plays an important role in suppressing EAT intensity, particularly on a bidecadal time scale. On the other hand, a warm anomaly in the west Pacific can enhance the intensity of the EAT, which is also reproduced by numerical simulation. The influence of a significant warming trend in the west Pacific and a weak positive trend in the AO on the EAT intensity and the East Asian winter monsoon is investigated. Warming in the west Pacific supports a strengthening of EAT intensity, cooling in northeast Asia, and enhancement of easterly wind in the subtropical west Pacific. A weak positive AO trend plays an insignificant role in affecting the trend of EAT intensity, but it supports warming in northeast Asia.
Improving the ESA CCI daily soil moisture time series with physically-based land surface model datasets using a Fourier time-filtering method
Authors: Seo Eunkyo , Dirmeyer Paul A. 
Published: January 2022

Abstract
Models have historically been the source of global soil moisture (SM) analyses and estimates of land-atmosphere coupling, even though they are usually calibrated and validated only locally. Satellite-based analyses have grown in fidelity and duration, offering an independent observationally-based alternative. However, satellite-retrieved SM time series include random and periodic errors that degrade estimates of land-atmosphere coupling, including correlations with other variables. This study proposes a mathematical approach to adjust daily time series of the European Space Agency (ESA) Climate Change Initiative (CCI) satellite SM product using information from physical-based land surface model (LSM) datasets using a Fourier transform time-filtering method to match the temporal power spectra locally to the LSMs, which tend to agree well with in situ observations.
When the original and time-filtered SM products are evaluated against ground-based SM measurements over the conterminous U.S., Europe, and Australia, results show the filtered SM has significantly improved subseasonal variability. The skill of the time-filtered SM is increased in temporal correlation by ∼0.05 over all analysis domains without introducing spurious regional patterns, affirming the stochastic nature of noise in satellite estimates, and skill improvement is found for nearly all land cover classes, especially savannas and grassland. Autocorrelation-based soil moisture memory (SMM), and the derived random component of soil moisture error (SME) are used to investigate the improvement of SM features. Time filtering reduces the random noise from the satellite-based SM product that is not explainable by physically-based SM dynamics; SME is usually diminished and the increased SMM is generally statistically significant.
Exploring the Essential Stroke Care Structures in Tertiary Healthcare Facilities in Rivers State, Nigeria
Authors: Osuegbu Osborne Ikechuckwu , Adeniji Foluke Olukemi , Owhonda Golden Chukwuemeka , Kanee Rogers Bariture , Aigbogun Eric Osamudiamwen 
Published: January 2022

This study evaluated the essential stroke care structure available in the two Tertiary Health Facilities in Rives State, Nigeria. This was a descriptive survey involving the Stroke Care Survey and Assessment Tool (checklist/questionnaire) developed by the World Stroke Organisation to obtain information about the available essential stroke care structure (facilities, equipment, personnel and management protocol) at the two tertiary health facilities (RSUTH & UPTH). The study gathered relevant information, which was summarised into tables and graphs using Microsoft Excel 2016. From the results, although facilities had A and E departments, dedicated stroke units (fixed or mobile) were unavailable, and there was no locally developed protocol to support rapid triage of stroke patients. The facilities and equipment were either unavailable or insufficient. Only one health facility (RSUTH) provided 24 hrs/7 days laboratory services. The workforces were a mix between regular clinical staff and some specialists. Tissue plasminogen activator (tPA) use was non-existent, though specialists were trained on its administration. There was no locally developed or adopted stroke-specific clinical guidelines. In conclusion, the structural services available for stroke care within the studied tertiary health facilities were poor, unavailable or grossly insufficient. The state facility (RSUTH) suffered the most in terms of unavailable national support and staff development.