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BACKGROUND/OBJECTIVES: Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. METHODS: Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. RESULTS: Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. CONCLUSIONS: Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.

[This corrects the article DOI: 10.1371/journal.pgen.1006012.].

Allotetraploid cotton species are a vital source of spinnable fiber for textiles. The polyploid nature of the cotton genome raises many evolutionary questions as to the relationships between duplicated genomes. We describe the evolution of the cotton genome (SNPs and structural variants) with the greatly improved resolution of 34 deeply re-sequenced genomes. We also explore the evolution of homoeologous regions in the AT- and DT-genomes and especially the phenomenon of conversion between genomes. We did not find any compelling evidence for homoeologous conversion between genomes. These findings are very different from other recent reports of frequent conversion events between genomes. We also identified several distinct regions of the genome that have been introgressed between G. hirsutum and G. barbadense, which presumably resulted from breeding efforts targeting associated beneficial alleles. Finally, the genotypic data resulting from this study provides access to a wealth of diversity sorely needed in the narrow germplasm of cotton cultivars.

Background/objectivesBone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche.MethodsMigration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry.ResultsEnhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment.ConclusionsOur results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.

Abstract Background This study introduces a novel surgical instrument to reduce iatrogenic nerve injuries during procedures such as carpal tunnel and ulnar nerve decompression surgery. These injuries often result from direct damage to surrounding tissues by surgical instruments, whose designs have remained largely unchanged over the past decades. The novel device is a modified surgical forceps that has a deployable surgical scalpel that runs along a groove on the forceps. This design protects important anatomical structures while allowing fast dissection and cutting of fascial layers. Methods The process used to develop a novel instrument included computer-aided design (CAD) modeling, 3D printing for prototyping, and the fabrication of an aluminum prototype. Biomechanical testing was performed with the novel device, iris scissors, bandage scissors, and a scalpel on an MTS Static Materials Test System. The peak force to slide-cut, number of cut attempts, and percentage cut on first attempt were compared between the prototype and traditional surgical tools. The materials cut in testing were Ace™ bandage, stockinette, and gauze. Statistical analyses were performed using Welch’s t-tests and Fisher’s exact tests. Results Compared to conventional bandage and iris scissors, the novel surgical instrument required significantly less force to cut through an Ace™ bandage, stockinette, and gauze (p

Abstract Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level. Graphic Abstract

Previous research demonstrated that lowdose endotoxin (LPS) administered during gestation can attenuate the postnatal response to LPS in weaned piglets. The follow-up study was designed to determine whether exposure to low dose LPS or a commercial Escherichia coli vaccine during gestation can alter immunity to an LPS challenge in piglets after weaning. Pregnant gilts were assigned to prenatal immune stimulation (PIS; n = 4; administered 2.5 µg/kg body weight (BW) LPS i.m. at d 77 ± 2.3 of gestation), vaccine (VAX; n = 3; administered LitterGuard-LTC i.m. at d 77 and 94 ± 1.7 of gestation), or saline treatment groups (CON; n = 3). From the three prenatal treatment groups, barrows (n = 13 PIS, 13 VAX, 14 CON) were identified at weaning (21 ± 1.9 d of age) to subsequently receive a post-weaning LPS challenge. On d -5, barrows were transported and housed in individual, indoor pens with ad libitum access to water and a starter ration. On d -1, pigs were fitted with indwelling jugular catheters and subcutaneous temperature loggers. On d 0, pigs were administered LPS (10 µg/kg BW i.v.), and blood samples were collected at -2, 0, 1, 2, 4, 6, 8, and 24 h relative to LPS challenge. Data were analyzed using PROC MIXED in SAS, specific for repeated measures. There was a tendency (P = 0.10) for a treatment effect for sow vaginal temperature, measured using indwelling logger, where PIS sows had greater vaginal temperature than CON sows, with VAX being intermediate. There was a treatment × time interaction (P = 0.02) for the change in lymphocyte concentration relative to pre-challenge values, where PIS piglets had less change in lymphocyte concentrations at 2 and 4 h compared with CON, and 8 h compared with CON and VAX piglets. Additionally, there was a treatment effect (P = 0.01) for neutrophil: lymphocyte ratio, where PIS piglets had a greater ratio compared with CON and VAX piglets. There was a treatment × time interaction (P = 0.04) for piglet subcutaneous body temperature, where PIS piglets had reduced temperature from 3 to 5 h compared with CON, and at 2 and from 4 to 7 h compared with VAX piglets. There was a tendency (P = 0.09) for a treatment effect for spleen length measured 24 h post-LPS administration where length was shorter in PIS compared with CON piglets, with VAX being intermediate. While data analysis continues for this study, these initial data support previous data suggesting an attenuated immune response to postnatal LPS when pigs are exposed to LPS in utero. Further, pigs exposed to an E. coli vaccine during gestation appear to respond similarly to CON pigs. These data add to available information on the ability to alter immunity of pigs in utero in an effort to positively influence piglet health after birth. [ABSTRACT FROM AUTHOR]

Liver abscesses (LA) continue to be an economic challenge for the beef industry. Chronic ruminal acidosis and ruminitis contribute to LA development. Fusobacterium necrophorum subsp. necrophorum, a ruminal bacterium, is the primary causative agent. Damaged ruminal, and possibly other gut regions, become susceptible to invasion and colonization by subsp. necrophorum, which reaches the liver via portal blood to cause abscesses. We hypothesize that the LA occurrence is related to the presence and concentrations of subsp. necrophorum in gut contents and epithelial tissues. Our primary objective was to detect, isolate and quantify subsp. necrophorum in gut contents and tissues in steers with experimentally induced LA. An experimental model, which included ruminal acidosis followed by intraruminal inoculation of subsp. necrophorum alone or with Salmonella enterica serotype Lubbock, was used to assess the relationship. Steers (n = 61) from three independent studies with three treatment groups were used. Treatments included: 1) forage-based diet with intraruminal inoculation of subsp. necrophorum; 2) ruminal acidosis with intraruminal inoculation of subsp. necrophorum; and 3) ruminal acidosis with intraruminal inoculation of subsp. necrophorum and S. Lubbock. Steers were euthanized 3 wk after bacterial inoculation and liver, gut contents, and tissue samples (ruminal, ileal and colonic) from steers with LA (n = 27) and with healthy livers (n = 34) were collected and subjected to culture method and quantitative PCR to isolate, detect, and quantify subsp. necrophorum. Data were analyzed by PROC GLIMMIX of SAS after summarizing frequency of isolation in various sample types within each study for steers with and without LA and converted to a binomial proportion. Concentrations were analyzed using steer as the experimental unit. The model included the fixed effect of liver status (abscessed or not) and study as the random effect. The frequency of isolation and mean concentration of subsp. necrophorum in purulent materials of LA were 100% and 3.5 x 107 Log10 CFU/g, respectively. The frequency of isolation of subsp. necrophorum from ruminal tissues of steers with LA was greater than steers with healthy livers (35.4 vs 14.5%; P = 0.04). Likewise, the concentration of subsp. necrophorum in ruminal tissues was greater in steers with LA than with healthy livers (4.2 vs 3.6 Log10 CFU/g; P < 0.001). None of the ileal and colonic tissues, except one ileal tissue in each group, yielded subsp. necrophorum. The concentrations of subsp. necrophorum in ruminal, ileal, and colonic contents did not differ (P = 0.9) between steers with LA or with healthy livers. Our data suggest that the occurrence of LA is positively related to prevalence and concentration of subsp. necrophorum in ruminal tissue, and the colonization likely serves as a source of continuous flow of bacterial emboli into the portal blood to initiate LA development. [ABSTRACT FROM AUTHOR]

This study aims to understand the club-fan relationship from the standpoint of club owners, CEOs, and head coaches (i.e., managers). Eight in-depth interviews were conducted with prominent figures from professional football and basketball in Israel. The current findings indicate that while clubs need the support of their fans, they often find themselves struggling with their aggressive behavior and demands to influence the club’s decision-making processes. First, this qualitative research provides an important insight into the unique experience of pivotal decision-makers in professional sports. Second, we apply the complexity lens to discuss the challenges faced by such stakeholders when trying to manage fans’ disruptive interventions.

BACKGROUND: Driving pressure (DP) and mechanical power (MP) may be important mediators of lung injury in ARDS; however, there is little evidence for strategies directed at reducing these parameters. We applied predictive modeling to estimate the effects of modifying ventilator parameters on DP and MP. METHODS: Two thousand six hundred twenty-two subjects with ARDS (Berlin criteria) from the Medical Information Mart for Intensive Care IV version 1.0 database admitted to the ICU at Beth Israel Deaconess Medical Center between 2008-2019 were included. Flexible confounding-adjusted regression models for time-varying data were fit to estimate the effects of adjusting PEEP and tidal volume (VT) on DP and adjusting VT and breathing frequency on MP. RESULTS: Reduction in VT reduced DP and MP, with more pronounced effect on MP with lower compliance. Strategies reducing frequency consistently increased MP (when VT was adjusted to maintain consistent minute ventilation). Adjustment of PEEP yielded a U-shaped effect on DP. CONCLUSIONS: This novel conditional modeling confirmed expected response patterns for DP, with the response to adjustments depending on subjects' lung mechanics. Furthermore, a VT-driven approach should be favored over a breathing frequency-driven approach when aiming to reduce MP. [ABSTRACT FROM AUTHOR]