Miracle-dz/UniFAR-FTUs huggingface dataset:
Cell-Type-Specific CRISPR/Cas9 Delivery by Biomimetic Metal Organic Frameworks.

Effective and cell-type specific delivery of CRISPR/Cas9 gene editing elements remains a chal-lenging open problem. Here we report the devel-opment of biomimetic cancer cell coated zeolitic imidazolate frameworks (ZIFs) for targeted and cell-specific delivery of this genome editing ma-chinery. Coating ZIF-8 that is encapsulating CRISPR/Cas9 (CC-ZIF) with cancer cell membrane resulted in the uniformly covered C3-ZIF(cell membrane type). Incubation of C3-ZIFMCF with MCF-7, HeLa, HDFn and aTC cell lines showed the highest uptake by MCF-7 cells and negligible uptake by the healthy cells (i.e. HDFn and aTC). As to genome editing, a 3-fold repression in the EGFP expression was ob-served when MCF-7 were transfected with C3-ZIFMCF compared to 1-fold repression in the EGFP expres-sion when MCF-7 were transfected with C3-ZIFHELA. In-vivo testing confirmed the selectivity of C3-ZIFMCF to accumulate in MCF-7 tumor cells. This supports the ability of this biomimetic approach to match the needs of cell-specific targeting which is unquestionably the most critical step in the future translation of genome editing technologies.
Intervening through Conversations: How Instructions Influence Conversational Valence and Binge Drinking Determinants

ABSTRACT A promising avenue for health behavior change is to influence conversational valence, that is, the extent to which people talk negatively or positively about health behaviors. However, no research to date has experimentally manipulated conversational valence, thereby inhibiting conclusions about causal inferences. This study aims to fill this gap by investigating the influence of conversational valence instructions on perceived conversational valence and subsequent binge drinking determinants. College students (N = 138) read either negative or positive conversational valence instructions. Subsequently, dyads engaged in a 5-min conversation about drinking, before self-reporting perceived conversational valence and binge drinking determinants (i.e., attitudes, norms, perceived behavioral control, and intentions). Results revealed that valence instructions influenced binge drinking determinants via perceived conversational valence. Those instructed to talk negatively about binge drinking reported healthier binge drinking determinants than those instructed to talk positively. Furthermore, this effect on binge drinking determinants was mediated by perceived conversational valence. These findings demonstrate that conversational valence about health can be manipulated through simple instructions and confirm the idea that conversational valence is causally linked to binge drinking determinants. Thereby, these findings show the potential that interpersonal communication in general, and conversational valence instructions, in particular, have when integrated in health interventions.
Subthalamic Nucleus Stimulation Impairs Motivation: Implication for Apathy in Parkinson's Disease

Apathy is one of the most disabling neuropsychiatric symptoms in Parkinson's disease (PD) patients and has a higher prevalence in patients under subthalamic nucleus deep brain stimulation. Indeed, despite its effectiveness for alleviating PD motor symptoms, its neuropsychiatric repercussions have not yet been fully uncovered. Because it can be alleviated by dopaminergic therapies, especially D2 and D3 dopaminergic receptor agonists, the commonest explanation proposed for apathy after subthalamic nucleus deep brain stimulation is a too‐strong reduction in dopaminergic treatments. The objective of this study was to determine whether subthalamic nucleus deep brain stimulation can induce apathetic behaviors, which remains an important matter of concern. We aimed to unambiguously address this question of the motivational effects of chronic subthalamic nucleus deep brain stimulation.
Fate of GdF3 nanoparticles-loaded PEGylated carbon capsules inside mice model: a step toward clinical application

Abstract The successful translation of nanostructure-based bioimaging and/or drug delivery system needs extensive in vitro and in vivo studies on biocompatibility, biodistribution, clearance, and toxicity for its diagnostic applications. Herein, we have investigated the in vitro cyto-hemocompatibility, in vivo biodistribution, clearance, and toxicity in mice after systemic administration of GdF3 nanoparticles loaded PEGylated mesoporous carbon capsule (GdF3-PMCC)-based theranostic system. In vitro cyto-hemocompatibility study showed a very good biocompatibility up to concentration of 500 µg/ml. Biodistribution studies carried out from 1 h to 8 days showed that GdF3-PMCC was found in major organs, such as liver, kidney, spleen, and muscle till 4th day and it was negligible in any tissue after 8th day. The clearance study was carried out for a period of 8 days and it was observed that the urinary system is the main route of excretion of GdF3-PMCC. The tissue toxicity study was done for 15 days and histopathological analysis indicated that the GdF3-PMCC based theranostic system does not have any adverse effect in tissues. Thus, PMCCs are nontoxic and can be applied as theranostic agents in contrast to the other carbon-based systems (PEGylated carbon nanotubes and PEGylated graphene oxide) which showed significant toxicity.
Non-Contrast CT and CT-Angiogram for Late Window Ischemic Stroke Treatment Selection

ABSTRACT: Introduction: The benefit of late window endovascular treatment (EVT) for anterior circulation ischemic stroke has been demonstrated using perfusion-based neuroimaging. We evaluated whether non-contrast CT (NCCT) and CT-angiogram (CTA) alone can select late-presenting patients for EVT. Methods: We performed a retrospective comparison of all patients undergoing EVT at a single comprehensive stroke center from January 2016 to April 2017. Patients planned for EVT were divided into early (<6 hours from onset) and late (≥6 hours from onset or last time seen normal) window groups. Incidence of symptomatic hemorrhagic transformations (sHTs) at 24 hours and 3-month modified Rankin scores (mRSs) were compared. Results: During the study period, 204 (82%) patients underwent EVT in the early and 44 (18%) in the late window. Median (interquartile range) NIH Stroke Scale Score was similar between groups (early: 18 [15–23] vs. late: 17 [13–21]), as were median ASPECT scores (early: 9 [8–10] vs. late: 9 [7–9]). In the late window, 42 (95%) strokes were of unknown onset. Similar proportions of sHT occurred at 24 hours (early: 12 [6%] vs. late: 4 [9%], p = 0.43). At 3 months, the proportion of patients achieving functional independence (mRS 0–2) were comparable in the early (80/192 [42%]) and late (16/41 [39%]) windows (p = 0.76). Conclusion: NCCT- and CTA-based patient selection led to similar functional independence outcomes and low proportions of sHT in the early and late windows. In centers without access to perfusion-based neuroimaging, this pragmatic approach could be safe, particularly for strokes of unknown onset.
The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: an analysis from the Ovarian Cancer Cohort Consortium (OC3).

Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per five-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity=0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity=0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from ~300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk which cumulates through life, suggesting this as an important area for identifying intervention strategies.
Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-onset Chronic Pancreatitis: TRPV6 and pancreatitis.

BACKGROUND AND AIMS Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. METHODS We performed whole-exome sequencing DNA from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (controls). In replication studies, we sequenced DNA from patients with early-onset CP (20 y or younger), not associated with alcohol consumption, from France (n=470) or Germany (n=410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. RESULTS We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13/300 cases (4.3%) and 1/1070 controls (0.1%) from Japan (OR, 48.4; 95% CI, 6.3-371.7; P=2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 controls (P=6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese cases vs controls (OR, 10.9; 95% CI, 4.5-25.9; P=7.4 × 10-9 for p.I223T; and P=.01 for p.D324N), whereas the p.L299Q was overrepresented in European cases vs controls (OR, 3.0; 95% CI, 1.9-4.8; P = 1.2 × 10-5). TRPV6mut/mut given cerulein developed more severe pancreatitis than control mice, demonstrated by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. CONCLUSIONS We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.
Portal Vein Thrombosis a Rare but Life-threatening Complication after Laparoscopic Sleeve Gastrectomy: A 5 Years Study in a Bariatric Center of Excellence.

BACKGROUND AND AIM Laparoscopic sleeve gastrectomy (LSG) is actually the most performed bariatric procedures in the world, and porto-mesenteric vein thrombosis (PVT) has been increasingly reported as a rare but serious complication. The best algorithm for PVT's prevention and therapy is still under discussion. The aim of this study is to explore the incidence and the outcomes of the PVT after LSG in a Bariatric Surgery Center of Excellence (BS-CoE) and elaborate a diagnostic and therapeutic algorithm for PVT after LSG. Methods: We retrospectively reviewed all the consecutive patients who underwent elective LSG within the last five years, between November 2014 and October 30th 2019, in Ponderas Academic Hospital, Bucharest, Romania. All the patients received an extended DVT prophylaxis protocol with adjusted doses of LMWH. Anti-factor Xa concentrations measurement to monitor the activity of LMWH in all the high-risk patients was used for the last two years. The patients suspected of PVT were scanned by computed tomography using IV contrast. All PVT patients were initially treated with systemic anticoagulation (Heparin), further interventions, such as systemic thrombolysis or surgery, being considered. After the acute stage, the PVT patients received longterm anticoagulation. Results: Of the 3861 patients who underwent elective LSG, three were readmitted 7-60 days after the bariatric procedure for PVT, equating to an incidence of 0.077%. The average age of the patients developing PVT was 40 years (SD 11.97), the average body mass index (BMI) was 40.34 (SD 7.994) kg/m2 and all of them underwent the same protocol for LSG. Two patients underwent conservative therapy with heparin anticoagulation and no surgery was needed. The third patient had a fulminant evolution in ICU, due to an extensive PVT, with death within two hours from his admission despite all resuscitation measures taken. The two patients remained on long life anticoagulant therapy. CONCLUSION A high clinical suspicion of PVT after LSG is required with prompt diagnosis and treatment. The BS-CoE protocol with adjusted doses of LMWH and extended prophylaxis proved to be very efficient showing a very low incidence of PVT.
Association of Ticagrelor vs Clopidogrel With Major Adverse Coronary Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Importance Guidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary events (MACE) vs clopidogrel but increased bleeding and dyspnea. Objective To compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE. Design, Setting, and Participants Population-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018. Exposures Outpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher. Main Outcomes and Measures Major adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea. Results Of 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 [36.4%]) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses. Conclusions and Relevance In this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.
Open Biceps Tenodesis: A Biomechanical Comparison of 6 Fixation Techniques.

Tenodesis is used to treat pathology of the long head of the biceps tendon. The authors evaluated the biomechanical properties of 6 techniques for biceps tenodesis fixation. The authors dissected 42 fresh-frozen cadaveric shoulders (mean age, 71±9.8 years; 69% male specimens), leaving the proximal humerus, proximal biceps tendon, and pectoralis major insertion. Specimens were randomized to undergo biceps tenodesis with one of the following: (1) an interference screw; (2) a cortical button; (3) a double-loaded 2.9-mm polyetheretherketone anchor (DL-2.9); (4) a double-loaded 1.9-mm all-suture anchor (DL-1.9); (5) a single-loaded 1.7-mm all-suture anchor (SL-1.7); or (6) soft tissue tenodesis. Specimens then underwent load-to-failure axial traction testing. A generalized linear and latent mixed model with a random-effects term was used to account for specimen pairing. Mean failure loads ranged from 136 N (95% confidence interval, 103-169 N) in the cortical button group to 79 N (95% confidence interval, 58-99 N) in the interference screw group. Failure occurred most often when fixation sutures pulled out of the tendon; however, 7 specimens failed elsewhere. No significant differences in ultimate failure load were found by treatment group. The interference screw group showed significantly more weakness than the cortical button and DL-2.9 groups. Tendon quality and suture parameters are likely more important than the fixation technique in determining failure load. [Orthopedics. 2020;43(x):xx-xx. ].
APOBEC3B expression in breast cancer cell lines and tumors depends on the estrogen receptor status.

Increased exposure to estrogen is associated with an elevated risk of breast cancer. Considering estrogen as a possible mutagen, we hypothesized that exposure to estrogen alone or in combination with the DNA-damaging chemotherapy drug, cisplatin, could induce expression of genes encoding enzymes involved in APOBEC-mediated mutagenesis. To test this hypothesis, we measured the expression of APOBEC3A (A3A) and APOBEC3B (A3B) genes in two breast cancer cell lines treated with estradiol, cisplatin, or their combination. These cell lines, T-47D (ER+) and MDA-MB-231 (ER-), differed by the status of the estrogen receptor (ER). Expression of A3A was not detectable in any conditions tested, while A3B expression was induced by treatment with cisplatin and estradiol in ER+ cells but was not affected by estradiol in ER- cells. In The Cancer Genome Atlas (TCGA), expression of A3B was significantly associated with genotypes of a regulatory germline variant rs17000526 upstream of the APOBEC3 cluster in 116 ER- breast tumors (p= 0.006) but not in 387 ER+ tumors (p= 0.48). In conclusion, we show that in breast cancer cell lines, A3B expression was induced by estradiol in ER+ cells and by cisplatin regardless of ER status. In ER+ breast tumors, the effect of estrogen may be masking the association of rs17000526 with A3B expression, which was apparent in ER- tumors. Our results provide new insights into the differential etiology of ER+ and ER- breast cancer and the possible role of A3B in this process through a mitogenic rather than the mutagenic activity of estrogen.
A truncating germline mutation of TINF2 in individuals with thyroid cancer or melanoma results in longer telomeres.

BACKGROUND Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here we further characterized the mutation and screened for coding variants in the six shelterin genes in 24 families. METHODS Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative RT-PCR was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes using quantitative real-time PCR. Whole exome sequencing (WES) was performed in 7 families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed using whole genome sequencing data from 17 families and WES data from 7 families. RESULTS The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families we identified 3 missense and 1 synonymous variant(s) in two shelterin genes (TINF2 and ACD). CONCLUSIONS The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.
EXPERIMENTAL ASSESSMENT OF NEW GENERATION OF URETERAL STENTS. BIODEGRADABLE AND ANTI-REFLUX PROPERTIES.

OBJECTIVE The aim is to assess a new biodegradable and anti-reflux intraureteral stent (BraidStent®) design in a swine model after ureteral laparoscopic surgery. MATERIAL AND METHODS A total of 24 female pigs were underwent initial endoscopic, nephrosonographic, and contrast fluoroscopy assessment of the urinary tract. Afterward, unilateral ureteropelvic junction obstruction was performed by laparoscopic approach. Six weeks later, the animals underwent laparoscopic Anderson-Hynes pyeloplasty, and were randomly assigned to Group-I, in which a double-pigtail ureteral stent was inserted for 6 weeks, or Group-II, in which a BraidStent®, a biodegradable intraureteral stent design, was placed. Follow-up assessments were performed at 3 and 6 weeks and 5 months. RESULTS In terms of therapeutic success, complete resolution was observed in 91.6% of Group-I animals and 88.8% in Group-II. No evidence of vesicoureteral reflux was observed in Group-II animals and statistical significance in vesicoureteral reflux and ureteral orifice damage were observed between groups. BraidStent® degradation occurred in a controlled manner between 3-6 weeks, without obstructive fragments. Distal ureteral peristalsis was maintained in 66.6% and 83.3% in Group-II at 3 and 6 weeks of follow-up, respectively. In Group-II, the positive bacteriuria rate was 41.6% and the migration rate 25%. Pathological assessment showed a significant improvement in ureteral healing in Group-II versus Group-I. CONCLUSIONS The results of this comparative study in a porcine model indicate that the intraureteral BraidStent® performed similarly to conventional ureteral stents. It avoids complete ureteral length intubation, the adverse effects associated with conventional ureteral stents and maintains a high level of distal ureteral peristalsis. Moreover, the BraidStent® exhibited a predictable and controlled degradation rate and did not cause any obstructive fragments. However, further studies will be needed to improve the anchoring system and reduce the risk of bacterial colonisation.