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Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis. Colorectal cancers (CRCs) often develop into untreatable metastatic disease of the liver. Here the authors report the modification of extracellular matrix proteins by citrullination in CRC metastases to the liver and propose that inhibition of citrullination could serve as therapeutic avenue in the treatment.

The COVID-19 pandemic confronted humans with high uncertainty and lockdowns, which severely disrupted people’s daily social and health lifestyles, enhanced loneliness, and reduced well-being. Curiosity and information-seeking are central to behavior, fostering well-being and adaptation in changing environments. They may be particularly important to maintain well-being during the pandemic. Here, we investigated which motives drive information-seeking, and whether and how curiosity and information-seeking related to well-being and mood (excitement, anxiety). Additionally, we tested whether daily diet contributed to this relationship during lockdown. Participants ( N  = 183) completed questionnaires measuring curiosity, information-seeking, social and mental health. Using a smartphone app, participants submitted their daily food intake and lifestyle ratings for a week. We found participants had highest motivation to seek positive (vs. negative) information, concerning themselves more than others. Both trait curiosity and information-seeking predicted higher well-being, mediated by loneliness. Trait curiosity also predicted well-being and excitement days later. Considering diet, participants with lower trait curiosity ate food containing more tyrosine (i.e., dopamine precursor). Furthermore, participants consuming food high in sugar reported higher anxiety, which was specifically found in participants with relatively low, but not high, trait curiosity. Taken together, curiosity and information-seeking may benefit well-being and mood in high uncertain and challenging times, by interacting with lifestyle measures (loneliness and nutrition).

Background: Emerging research suggests that immune responses may influence results after various orthopaedic operations. This study aimed to determine if similar relationships exist in meniscal allograft transplantation (MAT). Purpose: To compare clinical outcomes and failure rates for patients who underwent MAT based on presence or absence of self-reported drug allergies. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of patients who underwent MAT from January 2004 to December 2021 at a single academic medical institution was conducted with minimum follow-up of 2 years. Age, sex, body mass index, and presence of concomitant procedures were collected. The presence or absence of patient-reported allergies was recorded from the electronic medical record. Graft failure was defined as removal or revision of primary MAT, subsequent cartilage procedure, or progression to arthroplasty. The Lysholm score, International Knee Documentation Committee (IKDC) score, and all Knee injury and Osteoarthritis Outcome Score (KOOS) were compared for each patient from preoperative to 2-year time points. The minimal clinically important difference was determined using distribution-based method. Results: A total of 107 patients who underwent MAT with minimum follow-up of 2 years were included in the study. Of the total, 22 (20.6%) had self-reported ≥1 medication allergy and 85 (79.4%) did not report any medication allergies. There were no significant differences between the no-allergy and allergy cohorts in other demographic variables. There was no significant difference in failure rate between the no-allergy and allergy cohorts (18.1% vs 8.2%; P = .17). There were no statistically significant differences in Lysholm, IKDC, or KOOS subscales preoperatively or at 2 years postoperatively. Self-reported drug allergies did not serve as a significant risk factor for failing to achieve minimal clinically important difference across any outcomes in the patient population. Conclusion: The presence of self-reported drug allergies does not appear to adversely affect clinically significant outcome improvement or graft survival rates in patients undergoing MAT. These findings suggest that self-reported allergies should not be considered a limiting factor for MAT and that surgeons can continue to focus on other patient-specific factors that may be more predictive of postoperative outcomes.

Fatal problems encountered in allogeneic stem cell transplantation include EBV reactivation and post transplant lymphoproliferative disorders (PTLDs) with high mortality rates. We performed a retrospective analysis in all consecutive adult and pediatric EBV reactivations and PTLD during a period of 8.5 years. There were 26 patients with EBV reactivation/PTLD out of a total of 854 transplantations giving an overall incidence of 3.0%. Specifically, the incidence of EBV-PTLD was 1.3%, whereas that of EBV reactivation was 1.8%. Median age was 46.0 and 11.0 years in the adult and pediatric patients, respectively. There were high rates (54%) of concomitant bacterial, viral, fungal and parasitic infections at the time of EBV manifestation. Variable treatment regimens were applied including in most cases an anti-CD20 regimen often in combination with virustatic compounds, polychemotherapy or donor lymphocytes. The mortality rates were 9 of 11 (82%) in patients with EBV-PTLD and 10 of 15 (67%) in patients with reactivation. Only 7 of 26 patients (27%) are alive after a median follow-up of 758 days (range 24–2751). The high mortality rates of EBV reactivation and of EBV-PTLD irrespective of multimodal treatment approaches emphasize standardization and optimization of post transplant surveillance and treatment strategies to improve control of these often fatal complications.

The aim of this study was to determine if fescue toxicosis altered blood perfusion in the corpus luteum (CL) and peripheral concentrations of progesterone in cattle. The estrous cycles of 36 nonpregnant Angus or Charolais cows were synchronized in 2 replicates using the CO-Synch+CIDR protocol. Seven days after initiation of the protocol, cows were assigned (d 0) to 1 of 2 dietary treatments: 2.5 kg of 1) Kentucky-31 endophyte-infected (KY31; = 14) or 2) MaxQ novel endophyte (MaxQ; = 12) tall fescue seed. On d 7, ovaries were examined using ultrasonography, and only cows that had 1 CL present remained on the study ( = 26). Images of blood perfusion of CL, blood samples, rectal temperatures, and blood pressure of tails were collected on d 10, 13, 15, and 18. Images of CL blood perfusion were analyzed using ImageJ software for pixel density, and scored visually (0 to 9 with 0 = no perfusion, 9 = complete perfusion) by 2 independent technicians. The MIXED procedure of SAS was used with day as a repeated measure. Least squares means and SEM are reported. Cows receiving KY31 had greater rectal temperatures ( 0.003; 38.76 ± 0.08°C) than those receiving MaxQ (38.44 ± 0.08°C), providing evidence that the cows treated with KY31 were influenced by fescue toxicosis. Pulse pressure and mean arterial pressure were decreased ( < 0.01) in cows receiving KY31 (55.26 ± 2.81 and 80.06 ± 2.72 mmHg, respectively) than MaxQ (66.58 ± 3.03 and 91.38 ± 2.93 mmHg, respectively). Concentrations of progesterone were similar ( = 0.54) between cows receiving KY31 (6.04 ± 0.53 ng/mL) or MaxQ (6.36 ± 0.63 ng/mL). Pixel densities ( = 0.14) and visual perfusion scores were similar ( = 0.11) between cows receiving KY31 (1477.20 ± 655.62 pixels and 2.23 ± 0.34, respectively) or MaxQ (2934.70 ± 718.20 pixels and 3.00 ± 0.36, respectively). Mean CL volume was similar ( 0.95) between treatments. In conclusion, blood perfusion of CL or peripheral concentrations of progesterone were not altered at the onset of fescue toxicosis in this short-term study, indicating that a decrease in blood perfusion of the CL may not be a primary mechanism involved in decreased reproductive efficiency of cattle during fescue toxicosis.

Background Primary aldosteronism (PA) is the most common cause of secondary hypertension. Surgery is the mainstay of treatment for unilateral dominant PA, but reported cure rates varies. The aim of the present study was to investigate contemporary follow-up practices and cure rates after surgery for PA in Sweden. Methods Patients operated for PA and registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) 2009–2015 were identified. Patient data were extracted, and follow-up data (1–24 months) was recorded. Doses of antihypertensive medication and potassium supplementation were calculated using defined daily doses (DDD), and the Primary Aldosteronism Surgical Outcome (PASO) criteria were used to evaluate outcomes. Results Of 190 registered patients, 171 (47% female, mean age 53 years, median follow-up 3.7 months) were available for analysis. In 75 patients (44%), missing data precluded evaluation of biochemical cure according to the PASO criteria. Minimal invasive approach was used in 168/171 patients (98%). Complication rate (Clavien-Dindo >3a) was 3%. No mortality was registered. Pre/postoperatively 98/66% used antihypertensives (mean DDD 3.7/1.5). 89/2% had potassium supplementation (mean DDD 2.0/0) before/after surgery. Complete/partial biochemical and clinical success according to the PASO criteria were achieved in 92/7% and 34/60%, respectively. Conclusion In this study, reflecting contemporary clinical practice in Sweden complete/partial biochemical and clinical success after surgery for PA was 92/7% and 34/60%. Evaluation of biochemical cure was hampered by lack of uniform reporting of relevant outcome measures. We suggest mandatory reporting of surgical outcomes using the PASO criteria for all units performing surgery for PA.

The objectives of this experiment were to determine the effects of follicular wave (first or second) on diameter of the dominant follicle, concentrations of progesterone and estradiol and the hepatic enzymes that inactivate them, thickness of the endometrium, and pregnancy rates to AI. Beef heifers ( = 101) and cows ( = 106) were randomly assigned to 1 of 2 treatments: insemination to the first follicular wave (FFW) or insemination to the second follicular wave (SFW). Estrous cycles of females were synchronized to ensure appropriate timing for the treatments. The MIXED procedure of SAS was used for analysis. A similar proportion of females in each treatment responded to presynchronization; however, females in the FFW group ovulated in response to the first injection of GnRH of the CO-Synch protocol more frequently. Only females ( = 94) that properly responded to ovulation synchronization were included in further analyses. Cows in the FFW group tended ( 0.06) to have larger ovulatory follicles 36 h post-PGF of the CO-Synch protocol compared to cows in the SFW group (14.22 ± 0.42 and 11.83 ± 0.49, respectively), whereas heifers were similar between treatment groups. Three d prior to AI, circulating concentrations of progesterone were lesser ( 0.01) in females in the FFW (3.63 ± 0.80 ng/mL) than in the SFW (7.12 ± 0.83 ng/mL), whereas concentrations of estradiol tended ( 0.08) to be greater in those in the FFW (82.72 ± 6.48 pg/mL) than in the SFW (65.55 ± 6.74 pg/mL). Concentrations of cytochrome P450 1A in the liver were lesser ( 0.01) in females in the FFW than those in the SFW (0.68 ± 0.08 vs. 0.96 ± 0.06, respectively). Endometrial thicknesses were similar between treatments but were thicker ( < 0.0001) in cows (9.73 ± 0.24 mm) than heifers (7.22 ± 0.26 mm). When considering all females or only those that were properly presynchronized, pregnancy rates were similar between treatments. However, when evaluating females that ovulated to the assigned follicular wave, there was a treatment by parity interaction ( = 0.04) with heifers in the FFW having a lesser pregnancy rate (25.9%) than heifers in the SFW (72.0%) while cows in both treatment groups were intermediate (45.4% in FFW and 50.0% in SFW). The differences in concentrations of steroids between treatment groups may affect fertility of heifers; however, additional research is necessary.

A multilocation study examined pregnancy risk (PR) after delaying AI in suckled beef cows from 60 to 75 h when estrus had not been detected by 60 h in response to a 7-d CO-Synch + progesterone insert (CIDR) timed AI (TAI) program (d -7: CIDR insert concurrent with an injection of GnRH; d 0: PGF injection and removal of CIDR insert; and GnRH injection at TAI [60 or 75 h after CIDR removal]). A total of 1,611 suckled beef cows at 15 locations in 9 states (CO, IL, KS, MN, MS, MT, ND, SD, and VA) were enrolled. Before applying the fixed-time AI program, BCS was assessed, and blood samples were collected. Estrus was defined to have occurred when an estrus detection patch was >50% colored (activated). Pregnancy was determined 35 d after AI via transrectal ultrasound. Cows ( = 746) detected in estrus by 60 h (46.3%) after CIDR removal were inseminated and treated with GnRH at AI (Control). Remaining nonestrous cows were allocated within location to 3 treatments on the basis of parity and days postpartum: 1) GnRH injection and AI at 60 h (early-early = EE; = 292), 2) GnRH injection at 60 h and AI at 75 h (early-delayed = ED; = 282), or 3) GnRH injection and AI at 75 h (delayed-delayed = DD; = 291). Control cows had a greater ( < 0.01) PR (64.2%) than other treatments (EE = 41.7%, ED = 52.8%, DD = 50.0%). Use of estrus detection patches to delay AI in cows not in estrus by 60 h after CIDR insert removal (ED and DD treatments) increased ( < 0.05) PR to TAI when compared with cows in the EE treatment. More ( < 0.001) cows that showed estrus by 60 h conceived to AI at 60 h than those not showing estrus (64.2% vs. 48.1%). Approximately half (49.2%) of the cows not in estrus by 60 h had activated patches by 75 h, resulting in a greater ( < 0.05) PR than their nonestrous herd mates in the EE (46.1% vs. 34.5%), ED (64.2% vs. 39.2%), and DD (64.8% vs. 31.5%) treatments, respectively. Overall, cows showing estrus by 75 h (72.7%) had greater ( < 0.001) PR to AI (61.3% vs. 37.9%) than cows not showing estrus. Use of estrus detection patches to allow for a delayed AI in cows not in estrus by 60 h after removal of the CIDR insert improved PR to TAI by optimizing the timing of the AI in those cows.

NOTCH1 in heart disease A genetic basis for aortic valve calcification, a leading cause of heart disease in adults, has been discovered in a study of congenital heart disease in five generations of the same family. The disease was apparent in family members with a mutation in the transcriptional regulator NOTCH1 . The mutant gene causes heart valve defects in transgenic mice. NOTCH1 mutations have previously been identified in human blood cancers, but this is the first indication that it has a role in the development of the heart. Calcification of the aortic valve is the third leading cause of heart disease in adults 1 . The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1–2% of the population 2 . Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.