Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy of nimotuzumab (hR3) conjugated with 131I or 90Y in laryngeal carcinoma xenograft mouse model

Abstract Purpose The humanized monoclonal antibody hR3, both alone and in combination with other chemotherapeutic agents and radiotherapy, can be used to treat head and neck cancers. Substantial progress has been made in the development of targeted radioimmunotherapy using iodine-131 (131I) and yttrium-90 (90Y) radioisotopes in recent years. In the present study, we examined the efficacy of hR3 conjugated with 131I or 90Y to inhibit tumor growth in a laryngeal carcinoma xenograft tumor model. Methods hR3 was labeled with 131I or 90Y to generate the conjugates 131I-hR3 or 90Y-hR3. The conjugates were incubated with HEp-2 laryngeal carcinoma cells to evaluate binding capacity. The efficacy of the labeled hR3 conjugates to treat laryngeal cancer was also evaluated in nude mice inoculated with HEp-2 tumors. Results The purified radioimmunoconjugates with specific activities of 187–191 MBq/mg had radiochemical purity >98% and >80% immunoreactivity with HEp-2 cells. Mice with HEp-2 xenografts treated with 131I-hR3 or 90Y-hR3 showed reduced tumor volume and improved survival rates compared to the untreated control group and the group treated with unlabeled hR3. At equivalent doses, radioimmunotherapeutic hR3 labeled with 90Y had increased tumor inhibition activity compared to hR3 labeled with 131I. Conclusions 131I-hR3 and 90Y-hR3 are promising targeted radiopharmaceuticals for treatment of head and neck cancers, especially laryngeal cancers.
The Quality Analysis of Hallux Valgus Videos on YouTube.

BACKGROUND The aim of this study was to evaluate the information quality of YouTube videos on hallux valgus. METHODS A YouTube search was performed using the keyword 'hallux valgus' to determine the first 300 videos related to hallux valgus. A total of 54 videos met our inclusion criteria and evaluated for information quality by using DISCERN, Journal of the American Medical Association (JAMA) and hallux valgus information assessment (HAVIA) scores. Number of views, time since the upload date, view rate, number of comments, number of likes, number of dislikes, video power index (VPI) values were calculated to determine video popularity. Video length (sec), video source and video content were also noted. The relation between information quality and these factors were statistically evaluated. RESULTS The mean DISCERN score was 30.35{plus minus}11.56 (poor quality) (14-64), the mean JAMA score was 2.28{plus minus}0.96 (1-4), and the mean HAVIA score was 3.63{plus minus}2.42 (moderate quality) (0.5-8.5). Although videos uploaded by physicians had higher mean DISCERN, JAMA, and HAVIA scores than videos uploaded by non-physicians, the difference was not statistically significant. Additionally, view rates and VPI values were higher for videos uploaded by health channels, but the difference did not reach statistical significance. A statistically significant positive correlation was found between video length and DISCERN (r= 0.294, p= 0.028), and HAVIA scores (r= 0.326, p= 0.015). CONCLUSIONS This present study demonstrated that the quality of information available on YouTube videos about hallux valgus was low and insufficient. Videos containing accurate information from reliable sources are needed to educate patients on hallux valgus, especially in less frequently mentioned topics such as postoperative complications and healing period.
TDRD7 participates in lens development and spermiogenesis by mediating autophagosome maturation

ABSTRACT In humans, TDRD7 (tudor domain containing 7) mutations lead to a syndrome combining congenital cataracts (CCs) and non-obstructive azoospermia (NOA), characterized by abnormal lens development and spermiogenesis. However, the molecular mechanism underlying TDRD7’s functions in eye and testicular development are still largely unknown. Here, we show that the depletion of this gene in mice and humans resulted in the accumulation of autophagosomes and the disruption of macroautophagic/autophagic flux. The disrupted autophagic flux in tdrd7-deficient mouse embryonic fibroblasts (MEFs) was caused by a failure of autophagosome fusion with lysosomes. Furthermore, transcriptome analysis and biochemical assays showed that TDRD7 might directly bind to Tbc1d20 mRNAs and downregulate its expression, which is a key regulator of autophagosome maturation, resulting in the disruption of autophagosome maturation. In addition, we provide evidence to show that TDRD7-mediated autophagosome maturation maintains lens transparency by facilitating the removal of damaged proteins and organelles from lens fiber cells and the biogenesis of acrosome. Altogether, our results showed that TDRD7 plays an essential role in the maturation of autophagosomes and that tdrd7 deletion results in eye defects and testicular abnormalities in mice, implicating disrupted autophagy might be the mechanism that contributes to lens development and spermiogenesis defects in human. Abbreviations: CB: chromatoid bodies; CC: congenital cataract; CTSD: cathepsin D; DMSO: dimethyl sulfoxide; LAMP1: lysosomal-associated membrane protein 1; LECs: lens epithelial cells; MAP1LC3/LC3/Atg8: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; NOA: non-obstructive azoospermia; OFZ: organelle-free zone; RG: RNA granules; SQSTM1/p62: sequestosome 1; TBC1D20: TBC1 domain family member 20; TDRD7: tudor domain containing 7; TEM: transmission electron microscopy; WT: wild type.
Incidence and Mortality of Prostate Cancer in Canada during 1992–2010

In Canada, prostate cancer is the most common reportable malignancy in men. We assessed the temporal trends of prostate cancer to gain insight into the geographic incidence and mortality trends of this disease. Three independent population-based cancer registries were used to retrospectively analyze demographic data on Canadian men diagnosed with prostate cancer and men who died of prostate cancer between the years of 1992 and 2010. The incidence and mortality rates were calculated at the provincial, city, and forward sortation area (FSA) postal code levels by using population counts that were obtained from the Canadian Census of Population. The Canadian average incidence rate was 113.57 cases per 100,000 males. There has been an overall increasing trend in crude prostate cancer incidence between 1992 and 2010 with three peaks, in 1993, 2001, and 2007. However, age-adjusted incidence rates showed no significant increase over time. The national mortality rate was calculated to be 24.13 deaths per 100,000 males per year. A decrease was noted in crude and age-adjusted mortality rates between 1992 and 2010. Several provinces, cities, and FSAs had higher incidence/mortality rates than the national average. Several of the FSA postal codes with the highest incidence/mortality rates were adjacent to one another. Several Canadian regions of high incidence for prostate cancer have been identified through this study and temporal trends are consistent with those reported in the literature. These results will serve as a foundation for future studies that will seek to identify new regional risk factors and etiologic agents.
Long‐term outcomes of children with severe chronic pain: Comparison of former patients with a community sample

Findings on the short‐ and long‐term effectiveness of intensive interdisciplinary pain treatment (IIPT) for children with severe chronic functional pain are promising. However, a definitive appraisal of long‐term effectiveness cannot be made due to a lack of comparison groups. The aim of the present study was to compare the health status of former patients with the health status of an age‐ and sex‐matched comparison group from the community.
M‐wave and H‐reflex recruitment curves in boys and men

The aim of the present study was to check whether the M‐wave and H‐reflex recruitment curves differ between prepubertal boys and men. Eleven boys (9–11 yr) and eleven men (18–35 yr) were magnetically stimulated at the tibial nerve in a prone position. M‐wave and H‐reflex maximal amplitudes (Hmax; Mmax; Hmax/Mmax), thresholds, regression slopes (Hslp; Mslp; Hslp/Mslp) were extracted from M‐wave and H‐reflex recruitment curves and compared between the two age groups. Overall, no significant difference in M‐wave and H‐reflex recruitment curve parameters was found between the two populations. Nevertheless, the size of the M‐wave associated with maximal H‐reflex amplitude was lower in boys as compared to men when expressed relative to maximal M‐wave amplitude (MHmax/Mmax: 0.18 ± 0.06 vs. 0.31 ± 0.13; p < .05). This result suggests that the development of peripheral nerve was completed in 9 to 11‐year‐old boys and did not affect the M‐wave and H‐reflex recruitment curves parameters. In neuromuscular function studies, it implies that Hmax/Mmax and Hslp/Mslp could be used indifferently to compare spinal motoneuron excitability between 9–11‐year‐old boys and men. Conversely, evoking H‐reflexes at a given percentage of Mmax may bias the comparison between boys and men.
Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins

Background: Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered. Methods: The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case–control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. Results: Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (Ptrend < 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. Impact: The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.
European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations

Abstract Introduction Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence‐based guidelines to improve the medical care of patients suffering from this disorder. Methods Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method. Results These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence‐based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. Conclusion These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.
De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
How to Preserve Liver Grafts From Circulatory Death With Long Warm Ischemia? A Retrospective Italian Cohort Study With Normothermic Regional Perfusion and Hypothermic Oxygenated Perfusion

Supplemental Digital Content is available in the text. Background. Donation after circulatory death (DCD) in Italy, given its 20-min stand-off period, provides a unique bench test for normothermic regional perfusion (NRP) and dual hypothermic oxygenated machine perfusion (D-HOPE). Methods. We coordinated a multicenter retrospective Italian cohort study with 44 controlled DCD donors, who underwent NRP, to present transplant characteristics and results. To rank our results according to the high donor risk, we matched and compared a subgroup of 37 controlled DCD livers, preserved with NRP and D-HOPE, with static-preserved controlled DCD transplants from an established European program. Results. In the Italian cohort, D-HOPE was used in 84% of cases, and the primary nonfunction rate was 5%. Compared with the matched comparator group, the NRP + D-HOPE group showed a lower incidence of moderate and severe acute kidney injury (stage 2: 8% versus 27% and stage 3: 3% versus 27%; P = 0.001). Ischemic cholangiopathy remained low (2-y proportion free: 97% versus 92%; P = 0.317), despite the high-risk profile resulting from the longer donor warm ischemia in Italy (40 versus 18 min; P < 0.001). Conclusions. These data suggest that NRP and D-HOPE yield good results in DCD livers with prolonged warm ischemia.
The switching mechanism of the bacterial rotary motor combines tight regulation with inherent flexibility

Regulatory switches are wide spread in many biological systems. Uniquely among them, the switch of the bacterial flagellar motor is not an on/off switch but rather controls the motor’s direction of rotation in response to binding of the signaling protein CheY. Despite its extensive study, the molecular mechanism underlying this switch has remained largely unclear. Here, we resolved the functions of each of the three CheY‐binding sites at the switch in E. coli, as well as their different dependencies on phosphorylation and acetylation of CheY. Based on this, we propose that CheY motor switching activity is potentiated upon binding to the first site. Binding of potentiated CheY to the second site produces unstable switching and at the same time enables CheY binding to the third site, an event that stabilizes the switched state. Thereby, this mechanism exemplifies a unique combination of tight motor regulation with inherent switching flexibility.
Extension of an Atom–Atom Dispersion Function to Halogen Bonds and Its Use for Rational Design of Drugs and Biocatalysts

A dispersion function Das in the form of a damped atom–atom asymptotic expansion fitted to ab initio dispersion energies from symmetry-adapted perturbation theory was improved and extended to systems containing heavier halogen atoms. To illustrate its performance, the revised Das function was implemented in the multipole first-order electrostatic and second-order dispersion (MED) scoring model. The extension has allowed applications to a much larger set of biocomplexes than it was possible with the original Das. A reasonable correlation between MED and experimentally determined inhibitory activities was achieved in a number of test cases, including structures featuring nonphysically shortened intermonomer distances, which constitute a particular challenge for binding strength predictions. Since the MED model is also computationally efficient, it can be used for reliable and rapid assessment of the ligand affinity or multidimensional scanning of amino acid side-chain conformations in the process of rational design of novel drugs or biocatalysts.
Examining healthcare transition experiences among youth living with HIV in Atlanta, Georgia, USA: a longitudinal qualitative study

Virtually all youth living with HIV in paediatric/adolescent care must eventually transition to adult‐oriented HIV care settings. To date, there is limited evidence examining the perspectives of youth living with HIV longitudinally through the healthcare transition process. The objective of our study was to examine attitudes and experiences of youth living with HIV regarding healthcare transition, including potential change in attitudes and experiences over time.
DNase1L3 suppresses hepatocellular carcinoma growth via inhibiting complement autocrine effect.

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and currently lacks effective treatment strategies. The present study revealed that deoxyribonuclease 1 like 3 (DNase1L3) expression levels were significantly downregulated in numerous types of gastrointestinal cancer, and especially in HCC. Tissue microarrays were further used to illustrate that DNase1L3 expression levels were frequently downregulated in HCC tissues compared with normal liver tissues. In addition, DNase1L3 expression levels were identified to be significantly associated with tumor size (P = 0.0028), tumor thrombus formation (P < 0.01), and a poorer overall survival (P = 0.005) and disease-free survival (P = 0.006) of HCC. Gene Ontology functional term enrichment analysis of biological processes discovered that DNase1L3 was significantly associated with complement activation. Further studies demonstrated that the ectopic expression of DNase1L3 suppressed cell growth and inhibited the PI3K/AKT signaling pathway activation following C3a receptor agonist treatment. In conclusion, the findings of the present study suggested, for the first time, that DNase1L3 may serve as a biomarker for the prognosis of patients with HCC, and may suppress HCC growth via inhibiting the PI3K/AKT signaling pathway.
Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition

Purpose: Covalent inhibitors of KRASG12C specifically target tumors driven by this form of mutant KRAS, yet early studies show that bypass signaling drives adaptive resistance. Although several combination strategies have been shown to improve efficacy of KRASG12C inhibitors (KRASi), underlying mechanisms and predictive strategies for patient enrichment are less clear. Experimental Design: We performed mass spectrometry–based phosphoproteomics analysis in KRASG12C cell lines after short-term treatment with ARS-1620. To understand signaling diversity and cell type–specific markers, we compared proteome and phosphoproteomes of KRASG12C cells. Gene expression patterns of KRASG12C cell lines and lung tumor tissues were examined. Results: Our analysis suggests cell type–specific perturbation to ERBB2/3 signaling compensates for repressed ERK and AKT signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to coinhibition of SHP2 and SOS1. Conversely, both high basal and feedback activation of FGFR or AXL signaling were identified in mesenchymal cells. Inhibition of FGFR signaling suppressed feedback activation of ERK and mTOR, while AXL inhibition suppressed PI3K pathway. In both cell lines and human lung cancer tissues with KRASG12C, we observed high basal ERBB2/3 associated with epithelial gene signatures, while higher basal FGFR1 and AXL were observed in cells/tumors with mesenchymal gene signatures. Conclusions: Our phosphoproteomic study identified cell type–adaptive responses to KRASi. Markers and targets associated with ERBB2/3 signaling in epithelial subtype and with FGFR1/AXL signaling in mesenchymal subtype should be considered in patient enrichment schemes with KRASi.
Helping GPs to diagnose children's cancer.

in children and young people (CYP, aged <21 years), which contributes to GPs and paediatricians feeling inhibited from initiating cancer investigations until they are clearly progressive. This contributes to risk of delays in diagnosis and consequent adverse outcomes. As CYP constitute only 20%–25% of the population, it is estimated that a general practice will see a CYP with cancer every 1.8 years, an individual GP therefore may see only 1 per 5/10-year period.1 A recent review rephrased the risk of childhood cancer from a population perspective, to the risk for each child (Figure 1). This calculation shows that a child’s cancer risk rises from being very low (1 in 4700) in the first year of life, rising rapidly until 5 years of age (1 in 1000), achieving a moderate risk by 15 years (1 in 450) and a substantial risk by 20 years (1 in 320). These risks are comparable to risk of other common childhood conditions such as diabetes, epilepsy, and bacterial meningitis. Inherited factors play a part for a minority, associations with genetic conditions such as neurofibromatosis types 1 and 2, family cancer syndromes, and tissue overgrowth syndromes are established; rarer genetic mutations are being increasingly recognised.2 There is a demonstrable relationship between the age-incidence of different cancer types and the rate of physiological growth of the host tissues.3 The risk is highest in the first 5 years of life, when solid tumours and brain tumours together are more common than leukaemia. The combination of normal tissue growth and cancer development combines to make the cancers grow rapidly and present acutely. Delays can have profound clinical impact. These facts about risk mean that, while the risk of the individual GP making a diagnosis of cancer is very low, the risk for each child is significant. It is clearly not in the children’s interests for it to be disregarded. The GP needs diagnostic support with enhanced awareness, training, and guidelines relevant to current day practice.