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Salivary gland tissue engineering offers an attractive alternative for the treatment of radiation-induced xerostomia. Key to the success of this approach is the maintenance and expansion of secretory acinar cells in vitro. However, recent studies revealed that in vitro culture of primary salivary gland epithelial cells led to undesirable upregulation of the expression of keratin-7 (K7), a marker of ductal phenotype and frequently associated with cellular stress. We have previously shown that hyaluronic acid (HA)-based, RGDSP-decorated hydrogels support the 3D growth and assembly of primary human salivary gland stem/progenitor cells (hS/PCs). Here, we investigate whether the RGDSP culture also promotes K7 expression, and if so, what factors govern the K7 expression. Compared to hS/PCs maintained in blank HA gels, those grown in RGDSP cultures expressed a significantly higher level of K7. In other tissues, various transforming growth factor-β (TGF-β) superfamily members are reported to regulate K7 expression. Similarly, our immunoblot array and ELISA experiments confirmed the increased expression of TGF-β1 and growth/differentiation factor-15 (GDF-15) in RGDSP cultures. However, 2D model studies show that only TGF-β1 is required to induce K7 expression in hS/PCs. Immunocytochemical analysis of the intracellular effectors of TGF-β signaling, SMAD 2/3, further confirmed the elevated TGF-β signaling in RGDSP cultures. To maximize the regenerative potential of h/SPCs, cultures were treated with a pharmacological inhibitor of TGF-β receptor, A83-01. Our results show that A83-01 treatment can repress K7 expression not only in 3D RGDSP cultures but also under 2D conditions with exogenous TGF-β1. Collectively, we provide a link between TGF-β signaling and K7 expression in hS/PC cultures and demonstrate the effectiveness of TGF-β inhibition to repress K7 expression while maintaining the ability of RGDSP-conjugated HA gels to facilitate the rapid development of amylase expressing spheroids. These findings represent an important step towards regenerating salivary function with a tissue-engineered salivary gland.

Adventitial fibroblasts (AFs) are critical mediators of vascular remodeling. However, the contributions of AFs towards development of vasculature and the specific mechanisms by which these cells regulate physiological expansion of the vasa vasorum, the specialized microvasculature that supplies nutrients to the vascular wall, are not well understood. To determine the regulatory role of AFs in microvascular endothelial cell (MVEC) neovasculogenesis and to investigate the regulatory pathways utilized for communication between the two cell types, AFs and MVECs were cultured together in poly(ethylene glycol)-based hydrogels. Following preliminary evaluation of a set of cell adhesion peptides (AG10, AG73, A2G78, YIGSR, RGD), 7.5wt% hydrogels containing 3 mM RGD were selected as these substrates did not initiate primitive tubule structures in 3D MVEC monocultures, thus providing a passive platform to study AF-MVEC interaction. The addition of AFs to hydrogels promoted MVEC viability; however, increasing AF density within hydrogels stimulated MVEC proliferation, increased microvessel density and size, and enhanced deposition of basement membrane proteins, collagen IV and laminin. Importantly, AF-MVEC communication through the transforming growth factor beta (TGF-β)/activin receptor-like kinase 5 (ALK5) signaling pathway was observed to mediate microvessel formation, as inhibition of ALK5 significantly decreased MVEC proliferation, microvessel formation, mural cell recruitment, and basement membrane production. These data indicate that AFs regulate MVEC neovasculogenesis and suggest that therapeutics targeting the TGF-β/ALK5 pathway may be useful for regulation of vasculogenic and anti-vasculogenic responses.

Successful engineering of functional salivary glands necessitates the creation of cell‐instructive environments for ex vivo expansion and lineage specification of primary human salivary gland stem cells (hS/PCs). Herein, basement membrane mimetic hydrogels are prepared using hyaluronic acid, cell adhesive peptides, and hyperbranched polyglycerol (HPG), with or without sulfate groups, to produce “hyperGel+” or “hyperGel”, respectively. Differential scanning fluorescence experiments confirm the ability of the sulfated HPG precursor to stabilize fibroblast growth factor 10. The hydrogels are nanoporous, cytocompatible, and cell‐permissive, enabling the development of multicellular hS/PC spheroids in 14 days. The incorporation of sulfated HPG species in the hydrogel enhances cell proliferation. Culture of hS/PCs in hyperGel+ in the presence of a Rho kinase inhibitor Y‐27632 (Y‐27) leads to the development of spheroids with a central lumen, increases the expression of acinar marker aquaporin‐3 at the transcript level ( AQP3 ), and decreases the expression of ductal marker keratin 7 at both the transcript ( KRT7 ) and the protein levels (K7). Reduced expression of transforming growth factor beta (TGF‐β) targets SMAD2/3 is also observed in Y27‐treated cultures, suggesting attenuation of TGF‐β signaling. Thus, hyperGel+ cooperates with the Rho‐associated protein kinase inhibitor to promote the development of lumened spheroids with enhanced expression of acinar markers.

Adventitial fibroblasts (AFs) are critical mediators of vascular remodeling. However, the contributions of AFs towards development of vasculature and the specific mechanisms by which these cells regulate physiological expansion of the vasa vasorum, the specialized microvasculature that supplies nutrients to the vascular wall, are not well understood. To determine the regulatory role of AFs in microvascular endothelial cell (MVEC) neovasculogenesis and to investigate the regulatory pathways utilized for communication between the two cell types, AFs and MVECs were cultured together in poly(ethylene glycol)-based hydrogels. Following preliminary evaluation of a set of cell adhesion peptides (AG10, AG73, A2G78, YIGSR, RGD), 7.5wt% hydrogels containing 3 mM RGD were selected as these substrates did not initiate primitive tubule structures in 3D MVEC monocultures, thus providing a passive platform to study AF-MVEC interaction. The addition of AFs to hydrogels promoted MVEC viability; however, increasing AF density within hydrogels stimulated MVEC proliferation, increased microvessel density and size, and enhanced deposition of basement membrane proteins, collagen IV and laminin. Importantly, AF-MVEC communication through the transforming growth factor beta (TGF-[beta])/activin receptor-like kinase 5 (ALK5) signaling pathway was observed to mediate microvessel formation, as inhibition of ALK5 significantly decreased MVEC proliferation, microvessel formation, mural cell recruitment, and basement membrane production. These data indicate that AFs regulate MVEC neovasculogenesis and suggest that therapeutics targeting the TGF-[beta]/ALK5 pathway may be useful for regulation of vasculogenic and anti-vasculogenic responses.

Towards the goal of engineering an implantable salivary gland for the treatment of xerostomia, we culture primary human salivary gland stem/progenitor cells (hS/PCs) in hyaluronic acid (HA)-based hydrogels containing a covalently conjugate integrin-binding peptide (RGDSP). We characterize how RGDSP affects hS/PC phenotype and discover the presence of cells expressing both amylase and keratin-7 (K7) in our 3D cultures. Typically, amylase is expressed by acinar cells, and K7 is found in ducts. After assaying an array of transforming growth factor-β (TGF-β) superfamily members, we find increased expression of TGF-β1 and growth/differentiation factor-15 (GDF-15) in RGDSP cultures. However, 2D model studies confirm that only TGF-β1 is required to induce K7 expression in hS/PCs. We then demonstrate that with pharmacological inhibition of TGF-β signaling, K7 expression is repressed while amylase expression is maintained in RGDSP cultures. Thus, TGF-β signaling regulates K7 expression in hS/PCs, and modulation of TGF-β signaling is essential for the regeneration of salivary gland function. Competing Interest Statement The authors have declared no competing interest.

The strategies that experts have used to share information about social causes have historically been top-down, meaning the most influential messages are believed to come from planned events and campaigns. However, more people are independently engaging with social causes today than ever before, in part because online platforms allow them to instantaneously seek, create, and share information. In some cases this \"organic advocacy\" may rival or even eclipse top-down strategies. Big data analytics make it possible to rapidly detect public engagement with social causes by analyzing the same platforms from which organic advocacy spreads. To demonstrate this claim we evaluated how Leonardo DiCaprio's 2016 Oscar acceptance speech citing climate change motivated global English language news (Bloomberg Terminal news archives), social media (Twitter postings) and information seeking (Google searches) about climate change. Despite an insignificant increase in traditional news coverage (54%; 95%CI: -144 to 247), tweets including the terms \"climate change\" or \"global warming\" reached record highs, increasing 636% (95%CI: 573-699) with more than 250,000 tweets the day DiCaprio spoke. In practical terms the \"DiCaprio effect\" surpassed the daily average effect of the 2015 Conference of the Parties (COP) and the Earth Day effect by a factor of 3.2 and 5.3, respectively. At the same time, Google searches for \"climate change\" or \"global warming\" increased 261% (95%CI, 186-335) and 210% (95%CI 149-272) the day DiCaprio spoke and remained higher for 4 more days, representing 104,190 and 216,490 searches. This increase was 3.8 and 4.3 times larger than the increases observed during COP's daily average or on Earth Day. Searches were closely linked to content from Dicaprio's speech (e.g., \"hottest year\"), as unmentioned content did not have search increases (e.g., \"electric car\"). Because these data are freely available in real time our analytical strategy provides substantial lead time for experts to detect and participate in organic advocacy while an issue is salient. Our study demonstrates new opportunities to detect and aid agents of change and advances our understanding of communication in the 21st century media landscape.

Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma. In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1–21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m2 as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786. 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83–95). Complete responses occurred in 65 (63%, 95% CI 53–72) and partial responses in 28 patients (27%, 19–37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%]). Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress. Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant.

Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.

An unwelcoming climate and culture at scientific conferences is an obstacle to retaining scientists with marginalized identities. Here we describe how a number of professional societies in the plant sciences, mostly based in the United States, collaborated on a project called ROOT & SHOOT (short for Rooting Out Oppression Together and SHaring Our Outcomes Transparently) to make conferences in the field more inclusive. The guidelines we developed, and our efforts to implement them in 2023 and 2024, are summarized here to assist other conference organizers with creating more inclusive conferences.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes. Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease. Gene variation in type 2 diabetes Common variants at more than 80 genomic loci have been associated with susceptibility to type 2 diabetes, but together explain only a small fraction of the estimated heritability. Studies have hypothesized that rare or low-frequency genetic variation may explain a large proportion of the remaining disease risk. These authors now provide a test of this hypothesis in a large-scale sequencing study for type 2 diabetes conducted as part of the GoT2D and T2D-GENES projects. This work provides the most comprehensive view to date of the overall genomic architecture for disease risk, with the ability to examine the role for rare and low-frequency genetic variation. They find that most of the identified genetic risk variants were common and found in regions previously identified by genome-wide association studies.