bluuebunny/crossref_metadata_2025 huggingface dataset:
The Family‐Centred Practices Scale: Psychometric properties of the Spanish version for use with families with children with Down syndrome receiving early childhood intervention
Authors: Robles‐Bello María Auxiliadora , Sánchez‐Teruel David
Published: January 2022

Background

The Family‐Centred Practices Scale (FCPS) assesses the degree to which staff in early childhood intervention and development centres use this therapeutic approach. However, there is no adaptation of this scale to families of children with Down syndrome, which is one of the most prevalent intellectual disabilities in early intervention.

Objectives

To validate and analyse the psychometric properties of the FCPS in Spanish parents with children with Down syndrome receiving early childhood intervention.

Methods

Descriptive analyses, exploratory factor analysis (n = 131), confirmatory factor analysis (n = 126) and scale reliability analyses were performed. In addition, the invariance of the scale by parents' age and gender was assessed, and a longitudinal analysis of the scores was performed.

Results

A new scale was obtained with a two‐factor structure, similar to the original version, but with fewer items. Goodness‐of‐fit indices were excellent (root mean square error of approximation [RMSEA] [95% confidence interval {CI}] = 0.02 [0.01; 0.04]; comparative fit index [CFI] = 0.98; Tucker–Lewis index [TLI] = 0.97; root mean residual [RMR] = 0.02; goodness‐of‐fit index [GFI] = 0.91; adjusted GFI [AGFI] = 0.90). However, the measure was not gender invariant. Additionally, internal consistency of the two dimensions showed high values in this sample, and comparing the means between the two measurement time points (initial and at about 6 months) showed no differences; the test was powerful but had a very small effect size.

Conclusions

The psychometric properties of this FCPS are adequate, and it uses fewer items, which makes it faster to apply and gives it better clinical applicability. This new version of the scale is a valid, reliable tool for evaluating family‐centred practices in Spanish families with children with Down syndrome.
Truth and Responsibility in Expert Witnessing
Authors: Duncan Whitney L. , Reyes‐Foster Beatriz
Published: January 2022

Providing expert testimony in asylum proceedings for mentally ill Mexicans, we are regularly asked to reduce individual subjects to diagnostic categories and an entire country to one of its most dysfunctional institutions. How, attorneys and judges ask us, does Mexican “culture”—through its institutions and psychiatric hospitals—treat the mentally ill? To adjudicators of asylum claims, there must be a clear and often singular “truth.” As Nikolas Rose has argued, however, “Truth is always enthroned in acts of violence.” This essay grapples with a question inherent to this work: to whom—and to what truths—are anthropological expert witnesses responsible?
Three‐year extraction experience of a novel substernal extravascular defibrillation lead in sheep
Authors: Thompson Amy E. , Marshall Mark , Lentz Linnea , Mazzetti Hector
Published: January 2022

Background

The extravascular implantable cardioverter‐defibrillator (EV ICD) with lead implantation in the substernal space may provide an alternative to transvenous and subcutaneous systems. This is the first‐reported chronic extraction experience for EV ICD leads. The aim of the study is to evaluate the chronic encapsulation and extractability of EV ICD leads.

Methods

Two EV ICD leads and one transvenous lead were implanted in each of 24 mature sheep. A subset of animals was evaluated yearly for histology and lead extractability. Extractions were performed using simple traction or extraction tools. Histology evaluated the encapsulating tissue.

Results

At 1 year, extraction was performed successfully for two of five EV ICD leads with traction alone using ≤3.1 kg‐force (kgf) and the remainder extracted successfully with extraction tools; no transvenous leads were removed with traction alone. At 2 years, no EV ICD or transvenous leads were extracted with traction alone, while at 3 years, one of eight EV ICD leads and two of four transvenous leads were extracted with traction (0.8 and ≤2.3 kgf, respectively). There was one observation of hemopericardium resulting in tamponade with EV ICD extraction but without injury to cardiovascular structures and related to the unique implant tract. Among transvenous leads, inversion of the ventricle with loss of cardiac output resulted in abandonment of traction for two animals.

Conclusions

Chronic extraction of EV ICD leads from the substernal space was successfully performed using traction and simple tools through 3 years in sheep with one observation of hemopericardium that did not originate from cardiovascular injury.
Incidence of superficial abdominal organ identification is similar using high‐frequency linear (transrectal) and low‐frequency curvilinear (abdominal) transducers in clinically healthy horses: A pilot study
Authors: Haardt Hanna , Romero Alfredo E , Boysen Søren R , Lohnherr Anika , Tan Jean‐Yin
Published: January 2022

Abdominal organ displacement is a potentially life‐threatening condition in horses. Primary care veterinarians commonly make referral decisions based on a combination of clinical and ultrasonographic findings. However, published studies describing the effects of transducer on identifying abdominal organ locations in horses are currently lacking. The objective of this prospective, methods comparison, pilot study was to compare organ identification using a high‐frequency linear (transrectal) transducer and a low‐frequency curvilinear (abdominal) transducer for transcutaneous abdominal ultrasonography of healthy horses. Twelve clinically normal adult horses owned by the University of Calgary were enrolled in the study. Abdominal ultrasonography was performed by four practitioners, each randomly assigned to an alternating rotation of transrectal or abdominal transducer and left or right side of a horse. Using a Chi square test or Fisher's exact test, the frequency of identification for each organ was compared between both transducers. There was no significant difference in organ identification on the right side of the abdomen. On the left side, the stomach, liver, and kidney were less likely to be detected with the transrectal transducer. Compared with a low‐frequency abdominal transducer, a high‐frequency linear transrectal transducer delivers images that allow for organ identification in transcutaneous ultrasonography of the equine abdomen except for the left kidney, left liver, and stomach.
Overarching Themes in the Idra Rabba
Authors: Hellner-Eshed Melila
Published: January 2022

This chapter explores four overarching themes that connect the whole Idra Rabba: the mythic account of the emergence of many faces of the Divine; the unfolding of existence; various ways of attenuating the power of Judgment (Din); reading through the lens of consciousness, Oneness, and the dual male and female.
The Kings of Edom
Authors: Hellner-Eshed Melila
Published: January 2022

This chapter explores the myth of the kings of Edom from the Bible to the Zohar, its place in the Zohar, and its first appearance in the Idra Rabba.
Zeʿeir Anpin Comes into Being
Authors: Hellner-Eshed Melila
Published: January 2022

This chapter discusses God in the likeness of Adam (the human being), the emergence of Ze‘eir Anpin’s skull and brain.
The Tiqqunim of Zeʿeir Anpin
Authors: Hellner-Eshed Melila
Published: January 2022

This chapter is about the beard of Ze‘eir Anpin as an expression of divine attributes.
Forming the Male and Female Body
Authors: Hellner-Eshed Melila
Published: January 2022

This chapter explores the emanation of the divine masculine and feminine bodies, and the sources of the idraic myth of those bodies.
Modified Savonius Wind Turbine for Wind Energy Harvesting in Urban Environments
Authors: Le Anh Dinh , Minh Duc Banh , Van Hoang Tam , The Tran Hung
Published: January 2022

The flow-induced rotation of the modified Savonius rotor, for which the blade consists of a semicircular profile and an elliptical shape, is studied using a series of unsteady computational fluid dynamics (CFD) simulations. This study first concentrates on the validation of the numerical scheme against Blackwell's experimental data of the conventional rotor. The computed flow physics around the modified rotor with the same diameter is then analyzed and compared with that of the conventional rotor during one rotation cycle. As the result, the modified rotor is outperforming the conventional one but keeping its unique features. The modified rotor offers exceeding performance at a tip speed ratio (TSR) greater than 0.8. The new peak of the power coefficient Cp is reached at TSR = 1.4 which is a typical operating condition of the wind turbine in urban areas. The remarkable finding is that the suppression of the flow separation on the blade is an effective way to improve the rotor's aerodynamic performance. As expected, the additional elliptical profile plays a key role in increasing the positive torque and in preventing the flow separation on the blade, especially at high TSR > 0.8. Finally, this study points to not only advances the fundamental understanding of flow mechanism around the rotor but also proposes a good practical energy harvesting application in urban environments.
Ultrastructure and functional morphology of the mouthparts in Raoiella mites (Tetranychoidea: Tenuipalpidae): how they use the cheliceral stylets during feeding
Authors: Palma Antonella Di , Bauchan Gary R. , Beard Jennifer J. , Ochoa Ronald , Seeman Owen , Kitajima Elliot W.
Published: January 2022

The flat mite genus Raoiella Hirst (Tenuipalpidae) has attracted considerable research interest due to the rapid spread of Raoiella indica Hirst which feeds most commonly on species of palms (Arecaceae). Raoiella are frequently observed with their stylets inserted into the leaf stomatal openings, suggesting they feed on this site. Herein, we use transmission electron microscopy (TEM), scanning electron microscopy (SEM), low temperature scanning electron microscopy (LTSEM) and light microscopy (LM) to describe the mouthpart organization and the feeding behavior found in R. indica and R. bauchani Beard & Ochoa. The feeding mechanism is also discussed based on their distinctive morphological aspects. The structure of the gnathosoma of Raoiella generally agrees with the organization previously observed in Brevipalpus and Cenopalpus. As in other tetranychoid mites, there is no anatomical connection between the inter-stylet tube and the food channel, corroborating the theory that the stylets are used to pierce plant tissue (and assumedly inject saliva) but play no role in sucking up fluid from damaged host cells. As in Brevipalpus, the adoral setae are mechanoreceptors that may help guide the mite to the site for feeding. The ultrastructure of supracoxal setae e remains enigmatic. We also present observations of possible epidermal feeding on Phoenix roebelenii O'Brien (Arecaceae) for R. indica. Raoiella indica were shown to penetrate both the guard cells of the stomata and the epidermis of P. roebelenii, suggesting that feeding via the epidermis could be possible on this host plant.
Additions to the ptyctimous mite fauna (Acarina, Oribatida) of Nepal, with description of two new species of the family Steganacaridae
Authors: Niedbala Wojciech , Ermilov Sergey G.
Published: January 2022

The present study is based on ptyctimous mite materials collected from soil and litter in three forest localities in Nepal. A list of identified taxa, including 18 species from 12 genera and five families is provided; of these, two species (Oribotritia duotrisetosa, Plonaphacarus ishikawai) are recorded for the first time in the fauna of Nepal; two new species of Steganacaridae—Plonaphacarus othneios Niedbała sp. nov. and Hoplophthiracarus jochenmartensi Niedbała sp. nov.—are described. Oribotritia duotrisetosa sizes are given.
Supplemental Material: What drives Fe depletion in calc-alkaline magma differentiation: Insights from Fe isotopes
Authors: Du De-Hong , Wang Xiaolei , al. et
Published: January 2022

Methods, supplemental figures, and data.
Narratives of veterinary drug use in northern Tanzania and consequences for drug stewardship strategies in low-income and middle-income countries
Authors: Caudell Mark , Mangesho Peter E , Mwakapeje Elibariki R , Dorado-García Alejandro , Kabali Emmanuel , Price Cortney , OleNeselle Moses , Kimani Tabitha , Fasina Folorunso O
Published: January 2022

Introduction

Awareness-raising campaigns play a central role in efforts to combat drug resistance. These campaigns assume that knowledge deficits drive poor practices that increase resistance. Therefore, increasing awareness will promote prudent practices and reduce resistance. However, most awareness campaigns have been developed and evaluated in high-income and public health settings. Consequently, it is not clear whether these campaigns are effective in low-income and middle-income countries and/or within animal health settings.

Methods

Focus group discussions and in-depth interviews were used to collect narratives of veterinary drug use among Maasai pastoralists (n=70), animal health professionals (n=10) and veterinary drug sellers (n=5). Thematic analysis was used to identify recurring themes across narratives and groups.

Results

Narratives of Maasai and animal health professionals indicated that Maasai treated their livestock with limited input from the professional sector and that non-prudent treatment practices were observed (eg, using antimicrobials as ‘energizers’). Professionals linked these practices to knowledge and attitudinal deficits among the Maasai, while Maasai narratives highlighted the importance of climatic uncertainties and cultural beliefs surrounding veterinary care.

Conclusion

Narratives of veterinary drug use from animal health professionals are consistent with the knowledge deficit assumption guiding awareness-raising efforts. In contrast, Maasai narratives highlight how animal health practices are patterned by cultural norms interacting with factors largely outside of Maasai control, including a constrained professional veterinary sector. If these cultural and structural contexts remain unconsidered in awareness-raising strategies, current campaigns are unlikely to motivate practices necessary to limit drug resistance, especially within low-income and middle-income settings.
Abstracts from international emergency medicine journals
Authors: Production EMJ
Published: January 2022

Editor’s note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication.
Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer
Authors: Spadaccini Marco , Bourke Michael J , Maselli Roberta , Pioche Marhieu , Bhandari Pradeep , Jacques Jérémie , Haji Amyn , Yang Dennis , Albéniz Eduardo , Kaminski Michal Filip , Messmann Helmut , Herreros de Tejada Alberto , Sferrazza Sandro , Pekarek Boris , Rivory Jerome , Geyl Sophie , Gulati Shraddha , Draganov Peter , Shahidi Neal , Hossain Ejaz , Fleischmann Carola , Vespa Edoardo , Iannone Andrea , Alkandari Asma , Hassan Cesare , Repici Alessandro
Published: January 2022

Objective

Endoscopic submucosal dissection (ESD) in a curative intent for submucosa-invasive early (T1) colorectal cancers (T1-CRCs) often leads to subsequent surgical resection in case of histologic parameters indicating higher risk of nodal involvement. In some cases, however, the expected benefit may be offset by the surgical risks, suggesting a more conservative approach.

Design

Retrospective analysis of consecutive patients with T1-CRC who underwent ESD at 13 centres ending inclusion in 2019 (n=3373). Cases with high risk of nodal involvement (non-curative ESD: G3, submucosal invasion>1000 µm, lymphovascular involvement, budding or incomplete resection/R1) were analysed if follow-up data (endoscopy/imaging) were available, regardless of the postendoscopic management (follow-up vs surgery) selected by the multidisciplinary teams in these institutions. Comorbidities were classified according to Charlson Comorbidity Index (CCI). Outcomes were disease recurrence, death and disease-related death rates in the two groups. Rate of residual disease (RD) at both the previous resection site and regional lymph nodes was assessed in the surgical cases as well as from follow-up in the follow-up group.

Results

Of 604 patients treated by colorectal ESD for submucosally invasive cancer, 207 non-curative resections (34.3%) were included (138 male; mean age 67.6±10.9 years); in 65.2% of cases, no complete resection was achieved (R1). Of the 207 cases, 60.9% (n=126; median CCI: 3; IQR: 2–4) underwent surgical treatment with RD in 19.8% (25/126), while 39.1% (n=81, median CCI: 5; IQR: 4–6) were followed up by endoscopy in all cases. Patients in the follow-up group had a higher overall mortality (HR=3.95) due to non-CRC causes (n=9, mean survival after ESD 23.7±13.7 months). During this follow-up time, tumour recurrence and disease-specific survival rates were not different between the groups (median follow-up 30 months; range: 6–105).

Conclusion

Following ESD for a lesion at high risk of RD, follow-up only may be a reasonable choice in patients at high risk for surgery. Also, endoscopic resection quality should be improved.

Trial registration number

NCT03987828.
Stimulatory MAIT cell antigens reach the circulation and are efficiently metabolised and presented by human liver cells
Authors: Lett Martin J , Mehta Hema , Keogh Adrian , Jaeger Tina , Jacquet Maxime , Powell Kate , Meier Marie-Anne , Fofana Isabel , Melhem Hassan , Vosbeck Jürg , Cathomas Gieri , Heigl Andres , Heim Markus H , Burri Emanuel , Mertz Kirsten D , Niess Jan Hendrik , Kollmar Otto , Zech Christoph J , Ivanek Robert , Duthaler Urs , Klenerman Paul , Stroka Deborah , Filipowicz Sinnreich Magdalena
Published: January 2022

Objective

Mucosal-associated invariant T (MAIT) cells are the most abundant T cells in human liver. They respond to bacterial metabolites presented by major histocompatibility complex-like molecule MR1. MAIT cells exert regulatory and antimicrobial functions and are implicated in liver fibrogenesis. It is not well understood which liver cells function as antigen (Ag)-presenting cells for MAIT cells, and under which conditions stimulatory Ags reach the circulation.

Design

We used different types of primary human liver cells in Ag-presentation assays to blood-derived and liver-derived MAIT cells. We assessed MAIT cell stimulatory potential of serum from healthy subjects and patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt stent, and patients with inflammatory bowel disease (IBD).

Results

MAIT cells were dispersed throughout healthy human liver and all tested liver cell types stimulated MAIT cells, hepatocytes being most efficient. MAIT cell activation by liver cells occurred in response to bacterial lysate and pure Ag, and was prevented by non-activating MR1 ligands. Serum derived from peripheral and portal blood, and from patients with IBD stimulated MAIT cells in MR1-dependent manner.

Conclusion

Our findings reveal previously unrecognised roles of liver cells in Ag metabolism and activation of MAIT cells, repression of which creates an opportunity to design antifibrotic therapies. The presence of MAIT cell stimulatory Ags in serum rationalises the observed activated MAIT cell phenotype in liver. Increased serum levels of gut-derived MAIT cell stimulatory ligands in patients with impaired intestinal barrier function indicate that intrahepatic Ag-presentation may represent an important step in the development of liver disease.
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

Objective

Evidence 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.

Methods

We 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.

Results

There 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.

Conclusion

These 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

Background

Recombinant 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.

Methods

MDNA11 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).

Results

Binding 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.

Conclusion

MDNA11 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

Background

Immune 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.

Methods

A 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).

Results

The 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.

Conclusion

Our 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

Background

Immune 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.

Methods

Starting 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.

Results

Anti-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.

Conclusions

These 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.
Algebraic properties of face algebras
Authors: Calderón Fabio , Walton Chelsea
Published: January 2022

Prompted by an inquiry of Manin on whether a coacting Hopf-type structure [Formula: see text] and an algebra [Formula: see text] that is coacted upon share algebraic properties, we study the particular case of [Formula: see text] being a path algebra [Formula: see text] of a finite quiver [Formula: see text] and [Formula: see text] being Hayashi’s face algebra [Formula: see text] attached to [Formula: see text]. This is motivated by the work of Huang, Wicks, Won and the second author, where it was established that the weak bialgebra coacting universally on [Formula: see text] (either from the left, right, or both sides compatibly) is [Formula: see text]. For our study, we define the Kronecker square [Formula: see text] of [Formula: see text], and show that [Formula: see text] as unital graded algebras. Then we obtain ring-theoretic and homological properties of [Formula: see text] in terms of graph-theoretic properties of [Formula: see text] by way of [Formula: see text].
Analytic approach to a generalization of Chern classes in supergeometry
Authors: Roshandelbana M. , Varsaie S.
Published: January 2022

Some cohomology elements, called [Formula: see text]-classes, as a supergeneralization of universal Chern classes, are introduced for canonical super line bundles over [Formula: see text]-projective spaces, a novel supergeometric generalization of projective spaces. It is shown that these classes may be described by analytic representatives of elements of generalized de Rham cohomology.
Quasi-complemented posets
Authors: Joshi Vinayak , Mokbel Khalid
Published: January 2022

In this paper, several characterizations of quasi-complemented posets in terms of Baer ideals, 0-ideals, and minimal prime ideals are obtained. This extends the results of Jayaram, Cornish and Varlet. Further, we investigate the connections between Baer ideals, 0-ideals, and minimal prime ideals in the class of [Formula: see text], which extends the results of Jayaram. Moreover, for a given meet-semilattice [Formula: see text] in the class [Formula: see text], we prove that [Formula: see text] is weakly quasi-complemented if and only if each minimal prime ideal in [Formula: see text] contracts to a minimal prime ideal in [Formula: see text]. This extends the result of Cornish to meet-semilattices.
Some homological results for amalgamated duplication of Banach algebras
Authors: Ara Rana Jahan , Ostadbashi Saeid , Ebadian Ali , Jabbari Ali
Published: January 2022

Let [Formula: see text] and [Formula: see text] be two Banach algebras such that [Formula: see text] is a Banach [Formula: see text]-bimodule with the left and right compatible actions of [Formula: see text] on [Formula: see text]. Let [Formula: see text] be a strongly splitting Banach algebra extension of [Formula: see text] by [Formula: see text]. In this paper, we investigate some homological aspects such as injectivity, projectivity and flatness of [Formula: see text] and give some necessary and sufficient conditions for injectivity, projectivity and flatness of [Formula: see text].
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.
Electronic and Optical Properties of Mg2GeO4 under Pressure Effect: Ab Initio Study
Authors: Zhang Yunxia , Xiao Li’Na
Published: January 2022

We report first-principles studies of the structural, elastic, electronic, and optical properties of Mg2GeO4 in orthorhombic structure, including pressure dependence of structural parameters, band structures, density of states, and optical constants up to 20 GPa. The calculated structural parameters are in good agreement with the available experimental values at zero pressure. The mechanical stability of Mg2GeO4 has been confirmed by calculation of the elastic constants. And the non-uniform pressure dependence of the lattice parameters may also mean that Mg2GeO4 undergoes anisotropic compression. Meanwhile, the pressure dependence of the electronic band structure, density of states and partial density of states of Mg2GeO4 up to 20 GPa were presented. The band structures show a direct band gap for this compound and the calculated band gaps expend with increasing pressure. Moreover, the evolution of the dielectric function, absorption coefficient (

α

(
ω
)

), reflectivity (

R

(
ω
)

), and the real part of the refractive index (

n

(
ω
)

) at high pressure are also presented. According to our work, we found that the optical absorption spectra of Mg2GeO4 undergo a blue shift with increasing pressure.
Diaphragm muscle fibrosis involves changes in collagen organization with mechanical implications in Duchenne muscular dystrophy
Authors: Sahani Ridhi , Wallace C. Hunter , Jones Brian K. , Blemker Silvia S.
Published: January 2022

Scanning electron microscopy images of decellularized diaphragm muscle from WT and mdx, Duchenne muscular dystrophy model, mice revealed that collagen fibers in the epimysium are oriented transverse to muscle fibers, with age- and disease-dependent changes in collagen arrangement. Finite-element models generated from these images predicted that changes in collagen arrangement during disease progression influence the mechanical properties of the extracellular matrix. Thus, changes in collagen fiber-level structure are implicated on tissue-level properties during fibrosis.
A Modified Fifth-Order WENO-HLLC Riemann Solver for Transonic Viscous Flows around Helicopter Rotor in Hover
Authors: Xu Li , Zhao Fengfeng , Cai Jingjing
Published: January 2022

This paper presents a modified fifth-order WENO-HLLC Riemann solver for the transonic compressible viscous flows around the helicopter rotor in hover. The HLLC approximate Riemann solver is proposed to discrete the convection term involving grid velocity of the Navier-Stokes equations. In order to solve the interface flow accurately, a modified fifth-order WENO scheme is presented by designing the smoothness indicators based on

L

1

norm measurement. The improved WENO scheme can provide the optimal approximation order even at critical points. Numerical accuracy and robustness are validated by several benchmark inviscid flow problems. Then the numerical properties of the WENO-HLLC solver in conjunction with the implicit LU-SGS time integration method with high efficiency are further validated by simulating transonic viscous flows over RAE2822 airfoil and ONERA-M6 wing. The results show that the accuracy of calculating shock, discontinuity, and the vortex is significantly improved. Finally, the method is developed to compute the transonic vortex flow around the helicopter rotor with a domain discretized by overset grids. The results indicate that the proposed method is very robust and effective in acquiring high resolution for vortex wake.
Numerical Study of Leakage and Rotordynamic Performance of Staggered Labyrinth Seals Working with Supercritical Carbon Dioxide
Authors: Cao Hao , Zhang Wanfu , Yin Lu , Yang Li
Published: January 2022

The numerical model of a staggered labyrinth seal working with supercritical carbon dioxide (S–CO2) is established. The dynamic and static characteristics of the staggered labyrinth seal for different axial shifting distances of the rotor, various cavity geometries (heights/widths of the rotor convex plate, heights of the seal cavity), and seal clearances were investigated and compared with the conventional see-through labyrinth seal. The results show that the effective damping coefficient (Ceff) with positive axial shifting distance is higher than that with negative axial shifting distance. When the rotor with convex plate operates without axial shifting, the cross-coupled complex dynamic stiffness (hR) of the staggered labyrinth seal shows little effect on the Ceff, and the average direct damping (Cavg) has a dominant influence on the Ceff. As the whirling frequency (Ω) is lower than 60 Hz, the Ceff decreases with increasing height of the rotor convex plate. For Ω < 140 Hz, the damping coefficient generally increases with the decreasing height of the seal cavity. For Ω < 160 Hz, the Ceff of the see-through labyrinth seal is about 107%–649% of the staggered labyrinth seal. Otherwise, the Ceff of the staggered labyrinth seal is about 105%–113% of the see-through labyrinth seal. The Ceff of the seal with the rotor convex plate width of 5.13 mm is relatively high, which is conducive to the stability of the system. The Ceff increases with the decreasing seal clearance. The Ceff of the seal with 0.4 mm clearance is about 116%–148% the seal with 0.6 mm. The leakage flow rate of the staggered labyrinth seal of the see-through labyrinth seal is increased by about 45.5%. The leakage flow rate of the staggered labyrinth seal decreases with the increasing convex plate height, the seal cavity height, and the decreasing seal clearance.
Insecticidal, Antimalarial, and Antileishmanial Effects of Royal Jelly and Its Three Main Fatty Acids, trans-10-Hydroxy-2-decenoic Acid, 10-Hydroxydecanoic Acid, and Sebacic Acid
Authors: Alkhaibari Abeer Mousa , Alanazi Abdullah D.
Published: January 2022

Natural products and their derivatives as an inexpensive, accessible, and useful alternative medicine are broadly applied for the treatment of a wide range of diseases and infectious ones. The present study was designed to evaluate the insecticidal, antimalarial, antileishmanial, and cytotoxic effects of royal jelly and its three main fatty acids (trans-10-hydroxy-2-decenoic acid (10-H2DA), 10-hydroxydecanoic acid (10-HDAA), sebacic acid (1,10-decanedioic acid)). Insecticidal activity of RJ and 10-H2DA, 10-HDAA, and sebacic acid was performed against healthy 4th instar larvae at 25 ± 2°C. Antiplasmodial and antileishmanial effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid were also performed against chloroquine-resistant Plasmodium falciparum K1-strain and Leishmania major amastigotes according to the Malstat method and macrophage model, respectively. In addition, the level of nitric oxide (NO) production in J774-A1 macrophages cells, plasma membrane permeability, and caspase-3-like activity and cytotoxicity effects of RJ and 10-H2DA, 10-HDAA, and sebacic acid against human embryonic kidney 293 (HEK239T cells) were evaluated. Considering the insecticidal activity, the results showed that the lethal concentration 50% value for RJ, 10-H2DA, 10-HDAA, and sebacic acid was 24.6, 31.4, 37.8, and 44.7 μg/mL μg/mL, respectively. RJ, 10-H2DA, 10-HDAA, and sebacic acid showed potent (

P
<
0.0001

) antileishmanial effects with IC50 values ranging from 2.4 to 8.4 μg/mL. Various concentrations of RJ, 10-H2DA, 10-HDAA, and sebacic acid significantly (

P
<
0.05

) increased the production of NO, plasma membrane permeability, and caspase-3-like activity level as a dose-dependent response. Considering the cytotoxicity, SIs > 10 of these compounds exhibited their specificity to parasites and safety against human HEK239T normal cells. The results of the present investigation revealed the promising insecticidal, antimalarial, and antileishmanial effects of RJ and its three main fatty acids (10-H2DA, 10-HDAA, and sebacic acid). However, more studies are required to confirm the mechanisms of action mode of these compounds as well as their efficacy in animal models and clinical settings.
Method of Lagrange Multipliers for Normalized Zero Norm Minimization
Authors: Tausiesakul Bamrung
Published: January 2022

We present a normalization of the

p

-norm. A compressive sensing criterion is proposed using the normalized zero norm. Based on the method of Lagrange multipliers, we derive the solution of the proposed optimization framework. It turns out that the new solution is a limit case of the least fractional norm solution for

p
=
0

, where its fixed-point iteration algorithm can readily follow an existing algorithm. The derivation of the minimal normalized zero norm solution herein gives a relation in the aspect of Lagrange multiplier method to existing works that invoke least fractional norm and least pseudo zero norm criteria.
(+)-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

Identification 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.