Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel and Recurrent Mutations in a Cohort of Chinese Patients With Young-Onset Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. More than 25 ALS-related genes have been identified, accounting for approximately 10% of sporadic ALS (SALS) and two-thirds of familial ALS (FALS) cases. Several recent studies showed that genetic factors might have a larger contribution to young-onset ALS than to ALS cases overall. However, the genetic profile of young-onset ALS patients is not yet fully understood. Here, we investigated a cohort of 27 young-onset ALS patients (onset age < 45 years) through whole-exome sequencing (WES). Genetic analysis identified pathogenic variants of FUS (25.9%), SOD1 (22.2%), TARDBP (3.7%), and VCP (3.7%) in 27 young-onset ALS patients. Of 12 identified types of mutations, c.1528A > C in FUS and c.266G > A in VCP were novel. All of the cases in this study reflect a monogenic origin with an autosomal dominant mode of inheritance. Notably, a novel de novo missense mutation, c.1528A > C (p.K510Q), in FUS was identified in a 29-year-old ALS patient. Expression of the K510Q mutant FUS resulted in cytoplasmic mislocalization of FUS in cultured cells and induced neural toxicity in a fly model. This study provides further evidence of the genetic profile of young-onset ALS patients from China and expands the mutational spectrum of the FUS gene, with one new K510Q mutation identified.
Intrastriatal Memantine Infusion Dampens Levodopa-Induced Dyskinesia and Motor Deficits in a Mouse Model of Hemiparkinsonism

Although the administration of dopamine precursor levodopa remains as the mainstay for the treatment of Parkinson's disease, long-term exposure to levodopa often causes a disabling complication, referred to as levodopa-induced dyskinesias. Therefore, the development of new therapeutic interventions to dampen levodopa-induced dyskinesias and parkinsonian motor deficits is needed in the treatment of Parkinson's disease. Intracerebral brain infusion has the merit of being able to specifically deliver any drug into any brain part. By using an intracerebral infusion system equipped with implantable, programmable, and refillable pumps, we show herein that continuous intrastriatal administration of memantine (MMT), which is a non-competitive N-methyl-D-aspartate receptor antagonist, attenuates levodopa-induced dyskinesias and parkinsonian signs in 6-hydroxydopamine-lesioned hemiparkinsonian mice that received daily levodopa treatment. Corroborating the general thought that overactivation of the striatal N-methyl-D-aspartate receptor function might generate levodopa-induced dyskinesias and parkinsonism, our results suggest that a continuous intrastriatal MMT infusion can be beneficial for the management of Parkinson's disease with levodopa-induced dyskinesias. Our study also provides indications for the prototypic use of pharmacological deep-brain modulation through intracerebral infusion systems for treating medically intractable movement disorders.
A Critical Analysis of Intimate Partner Sexual Violence in Iran

According to global data, intimate partner violence and its corresponding impact threaten the lives of almost 35% of women at some point in their life. The aim of this research was to explore the effects of intimate partner sexual violence on women’s sense of self-efficacy when it comes to speaking out against violence and seeking help. In-depth interviews and a thematic analysis approach were employed to collect and analyze the data. The participants were 10 women with experiences of intimate partner sexual violence. They were selected through purposive and snowball sampling. Two main themes were drawn from the data, including Exposure and Empowerment. Exposure refers to the type of violence women have experienced and its physical and emotional effects; and Empowerment refers to factors women considered as giving them the courage to speak out against perpetrators, to seek help from others, or to refrain from doing either. It is concluded that Iranian women are not passive when exposed to intimate partner sexual violence, and social support, mainly from family and friends, was a pathway to feelings of empowerment; without this support, women’s emotional health is put in jeopardy. Due to the importance of social networks in creating a sense of empowerment, it is recommended that professionals involved in cases of intimate partner sexual violence create an alliance with the women’s families and friend and educate them on how to prevent violence or offer help before the violence takes its toll on woman’s emotional and physical wellbeing.
Specialized Therapeutic Assessment-Based Recovery-Focused Treatment for Young People With Self-Harm: Pilot Study

Background: Suicide is the second leading cause of death in young people worldwide. Self-harm is the strongest predictor of death by suicide. There is increasing evidence that psychological therapies are efficacious in treating self-harm in adolescents. However, studies so far have predominantly focused on highly selective groups of adolescents and have investigated interventions that require intensive training and considerable expense. Methods: We conducted a pilot study of a novel psychological therapy package, Specialized Therapeutic Assessment-Based Recovery-Focused Treatment (START) that consists of Therapeutic Assessment followed by treatment in one of three modules, depending on adolescents’ needs and preferences: Solution Focused Brief Therapy, Cognitive Behavior Therapy (CBT), or Mentalization Based Treatment. Adolescents (12–17) with at least one self-harm episode in the previous 6 months referred for community treatment, who had no intellectual disability, psychosis or autism were eligible for START. The primary outcome measure was the number of self-harm (regardless of suicidal intent) episodes 6 months before and 6 months after commencing START. Secondary outcomes included measures of psychopathology, functional impairment and family satisfaction. Results: Twenty-one consecutively referred adolescents were recruited and 15 received a therapeutic module of START: three received Solution Focused Brief Therapy, nine CBT, and three Mentalization Based Treatment. There was a statistically significant reduction in the number of self-harm episodes from a mean of 7.93 (SD = 12.26) to 1.00 (SD = 1.47), p < 0.02 following START. There was also a significant reduction in self-harm episodes, Revised Children’s Anxiety and Depression Scale scores and a statistically significant improvement in Children Global Assessment Scale scores for the CBT group alone. There were no significant differences in any other outcomes. Most families were somewhat or very much satisfied with the intervention. Conclusion: The results show that START was associated with a reduction in self-harm and depression and anxiety symptoms, which could indicate that START should be rigorously studied in a randomized control trial (RCT). However, the model had difficulties in its implementation, with CBT being only module that was offered to enough young people to allow before and after analysis. CBT appears to be the most promising module in treating adolescents with self-harm referred to community mental health services.
Um processo para elicitar requisitos de software em projeto de implantação de ERP para empresas com unidades autônomas e diferentes culturas organizacionais

Resumo. Os aspectos do processo para elicitação de requisitos na implantação de sistema ERP (Enterprise Resource Planning) são diferentes daqueles para desenvolvimento de um novo produto. Quando se trata da implantação deve-se ter atenção nas diferenças entre os processos de negócio e as funcionalidades oferecidas pelo sistema a ser implantado. Desalinhamentos em excesso pode tornar o projeto inviável. Diferentes culturas organizacionais e subdivisões empresariais com alto nível de autonomia são algumas das principais causas de insucesso na implantação de sistemas corporativos. Esta pesquisa tem como objetivo propor um modelo de processo para adequar as solicitações do cliente, diferentes ou ausentes no sistema a ser implantado, às necessidades reais da organização. Os resultados obtidos com a revisão sistemática possibilitaram a definição do modelo proposto, formado por técnicas identificadas na literatura e adaptadas ao contexto apresentado. O processo teve sua eficácia comprovada por meio do método de pesquisa-ação e foi aplicado em ambiente real de implantação, no decorrer da fase de elicitação de requisitos.
Rating the environmental and genetic risk factors for colorectal cancer

Colorectal cancer (CRC) is a disease preventable in up to 50% of the patients by lifestyle modifications. The preventive strategy for the decrease in the incidence and mortality of CRC is based on understanding the relations between the environmental and genetic factors. The most important identified risk factors for CRC are aging, personal and familial history of CRC or adenomas, hereditary colon cancer syndromes, dietary patterns, and inflammatory bowel disease. The purpose of this review is to update data referring to environmental and genetic documented factors and CRC risk. Using data from the Medline database, we analyzed reports on CRC risk published between 2000 and 2010. We realized a classification taking into consideration the relative risk (RR) reported for each analyzed factor (RR ranged between 1 and 6.87). The highest RR were represented by the patients with distal advanced cancer (RR = 6.7) and those with high dysplasia adenomas (RR = 6.87). In the future, evaluation and optimisation of screening options will stay at the base of new prevention strategies that will be implemented based on the influence of risk factors identified in each population.
Importance of assessing cytogenetic and molecular risk factors in acute myeloid leukemia therapy

Acute myeloid leukemia (AML) is a heterogeneous disease in clinical presentation, outcome and therapeutic response. Cytogenetic and molecular characteristics are important prognostic indicators allowing the identification of distinct subtypes of AML, prognostic stratification and risk-adapted treatment. We present our experience during 5 years, in which we treated 245 patients with AML, of which we could genetically characterize 48 cases (26 females, 22 males) with a median age of 52 years. Cytogenetic analysis was performed by GTG banding on cultures of marrow cells treated with colcemid. Molecular analysis used RT-PCR performed on ABI 9700 platform in order to identify the following fusion genes: E2A-PBX1, TEL-AML1, AML1-ETO, PML-RARα, MLL-AF4, CBFC-MYH11, BCR-ABL, SIL-TAL, and MLL-AF9as well as mutations in Flt3, NPM1, WT1 genes. Fourteen patients were older than 60 years. In 12 we performed cytogenetic analysis showing 5 cases with complex karyotype, 2 normal karyotypes, 1 case of del(21), del (9), 11q- and t(3;15) respectively as well as 2 unevaluable karyotypes. These anomalies were associated with a high incidence of secondary AMLs (10/14) and with a low remission (CR) rate (5/14). Out of the 35 patients younger than 60 years, 25 were evaluated by cytogenetics showing a high incidence of favorable cytogenetic changes: 6 anomalies of chromosome 16 (5 inv (16) and 1 t (16; 16)), 3 t (15; 17), 3 cases of t (8; 21) of which 2 with additional abnormalities, 7 normal karyotypes and 1 case of 7q-, -y,-3 and respectively -8 associated with +18. In 25 cases molecular analysis was performed showing alterations in 21 patients: 6 cases with AML/ETO, 3 PML/RAR, 7 Flt3 mutations (2 associated with NPM1 mutation) as well as 1 case of isolated mutation of NPM1 and respectively WT1. CR rate was of 28/35. All cases with t (15; 17) and PML/RAR as well all cases with t (8; 21) and/or AML/ETO achieved CR. Out of the 7 cases with Flt3 mutations only 4 achieved CR including the 2 cases with associated NPM1 mutations. In our experience, genetic characteristics correlate with other prognostic markers such as age and secondary leukemia; “favorable” genetic anomalies were associated with a high CR rate; association of t (8; 21) with additional abnormalities did not influence CR rate.
A novel technique for fabricating antibiotic-coated intramedullary nails using an antibiotic-loaded calcium sulphate hydroxyapatite bio-composite, Cerament-V

Abstract Deformity correction in the setting of osteomyelitis is a challenge for any orthopaedic surgeon. Principles of management are well described and include staged debridement, stable fixation and a combination of local and systemic antibiotic therapy. An antibiotic-coated nail (ACN) can prove a useful tool—stabilizing bone, whilst allowing for local antibiotic elution. Typically, the surgeon will prepare these implants in the operating room using materials that are routinely at hand. Most frequently, this will involve the use of antibiotic-loaded poly-methyl methacrylate (PMMA). This method of ACN fabrication has several disadvantages. PMMA is non-degradable and can be difficult to remove surgically. There are limitations with regard to antibiotic suitability, antibiotic release as well as toxicity effects. In this case report, we present a novel technique for the preparation of ACNs for use in hindfoot surgery, using a calcium sulphate/hydroxyapatite-based bio-composite—Cerament-V.
Serum Derived Exosomes From Pancreatic Cancer Patients Promoted Metastasis: An iTRAQ-Based Proteomic Analysis

Background Pancreatic cancer (PC) is one of the most aggressive malignancies and has a poor prognosis despite being extensively researched. The role of serum-derived exosomes in tumorigenesis and the development of PC is still unclear. Method The present study employed iTRAQ-based proteomic analysis to search for differences between the serum exosomes of PC patients and those from control patients. Then, bioinformatics methods were used to analyze the functions of the identified proteins, and the possible functions were verified through cell culture experiments. Results A total of 611 proteins were identified from exosomes, and 141 proteins were differentially expressed, with 91 up- and 50 down regulated proteins in PC cancer compared to healthy controls. Further analysis indicated that APOE serves as an important hub in the network. In addition, CRP, VWF, APOA2, NIN, and GSK3B potentially interact with many other proteins. We then tested the effect of patient serum-derived exosomes on pancreatic cancer cells and found that patient serum-derived exosomes, but not those from healthy controls, induced cell proliferation, migration, and EMT, supporting the role of exosomes in metastasis. Conclusion Our data suggest that exosomes derived from PC patients may promote PC metastasis.
Concepts Driving Pharmacogenomics Implementation Into Everyday Healthcare

: Pharmacogenomics (PGx) is often promoted as the domain of precision medicine with the greatest potential to readily impact everyday healthcare. Rapid advances in PGx knowledge derived from extensive basic and clinical research along with decreasing costs of laboratory testing have led to an increased interest in PGx and expectations of imminent clinical translation with substantial clinical impact. However, the implementation of PGx into clinical work ﬂ ows is neither simple nor straightforward, and comprehensive processes and multidisciplinary collaboration are required. Several national and international institutions have pioneered models for implementing clinical PGx, and these initial models have led to a better understanding of unresolved challenges. In this review, we have categorized and explored the most relevant of these challenges to highlight potential gaps and present possible solutions. We describe the ongoing need for basic and clinical research to drive further developments in evidence-based medicine. Integration into daily clinical work ﬂ ows introduces new challenges requiring innovative solutions; speci ﬁ cally those related to the electronic health record and embedded clinical decision support. We describe advances in PGx testing and result reporting and describe the critical need for increased standardization in these areas across laboratories. We also explore the complexity of the PGx knowledge required for clinical practice and the need for educational strategies to ensure adequate understanding among members of current and future healthcare teams. Finally, we evaluate knowledge obtained from previous implementation efforts and discuss how to best apply these learnings to future projects. Despite these challenges, the future of precision medicine appears promising due to the rapidity of recent advances in the ﬁ eld and current multidisciplinary efforts to effectively translate PGx to everyday clinical practice.
Identifying successful biomarkers for patients with non-small-cell lung cancer

Alex Friedlaender1, Joshua Bauml2, Giuseppe Luigi Banna3 & Alfredo Addeo*,1 1Department of Oncology, University Hospital of Geneva (HUG), 12052, Switzerland 2Abramson Cancer Center, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA 191043, USA 3Oncology Department, United Lincolnshire Hospital Trust, Lincoln, LN2 5QY, UK *Author for correspondence: Alfredo.Addeo@hcuge.ch
A squalamine derivative, NV669, as a novel PTP1B inhibitor: in vitro and in vivo effects on pancreatic and hepatic tumor growth

NV669 is an aminosterol derived from squalamine found to possess strong anticancer effects. The aim of this study was to investigate NV669’s beneficial effects on human pancreatic and hepatic cancer models and to decipher the cellular and molecular mechanisms involved in tumor growth decrease upon treatment with NV669. Pancreatic (BxPC3, MiaPaCa-2) and hepatic (HepG2, Huh7) cancer cells were treated with NV669, and the effects recorded on proliferation, cell cycle and death. Results showed that NV669 inhibited the viability of cancer cells, induced cell cycle arrest and subsequently promoted apoptosis. This was accompanied by a decrease in the expression of cyclin B1 and phosphorylated Cdk1 and by a cleavage of pro-apoptotic caspase-8 and PARP-1. Taken together, our studies showed that NV669 inhibits the proliferation of pancreatic and hepatic cancer cells through the regulation of G2/M phase transition via the cyclin B1-Cdk1 complex. In vitro NV669 inhibits PTP1B activity and FAK expression. NV669 impacts on the expression of adhesion molecules CDH-1, -2 and -3 in BxPC3 and Huh7 lines that form cell monolayers. Consecutively NV669 induces cell detachment. This suggests that NV669 by inhibiting PTP1B induces cell detachment and apoptosis. Subsequently, our in vivo results showed that NV669 inhibited the growth of pancreatic and hepatic tumor xenografts with a significant cell cycle arrest in pre-mitotic phase and an increase of tumor cell apoptosis. Therefore, NV669 may serve as an alternative anticancer agent, used alone or in association with other medications, for the treatment of pancreatic adenocarcinoma and hepatocellular carcinoma.
Real life efficacy and safety of direct-acting antiviral therapy for treatment of patients infected with hepatitis C virus genotypes 1, 2 and 3 in northwest China

BACKGROUND Regimens involving direct-acting antiviral agents (DAAs) are recommended for the treatment of infection with hepatitis C virus (HCV) genotypes 1, 2 and 3. But real-world data is still not enough, especially in Asia. AIM To investigate the efficacy and safety of DAA-based regimens in a real-life setting in China. METHODS This study included 366 patients infected with HCV genotypes 1, 2 and 3, with or without cirrhosis, who were observed between May 2015 and December 2018. They were treated with ledipasvir and sofosbuvir (SOF) (genotype 1) with or without ribavirin (RBV), SOF and RBV (genotype 2), or SOF and daclatasvir (genotype 3), with or without RBV, for 12 or more wk. The participants’ sustained virological responses (SVR) at post-treatment week 12 (SVR12) was the primary endpoint. The occurrence of adverse events and drug-drug interactions were recorded. RESULTS In the 366 patients, genotype 1 (59.0%) was the most common genotype, followed by genotypes 2 (34.4%) and 3 (6.6%). Liver cirrhosis was diagnosed in 154 (42.1%) patients. Fifty (13.7%) patients were treatment-experienced. Intention-to-treat analysis revealed that SVR12 was 86.3% (316/366). For modified intention-to-treat analysis, SVR12 was achieved in 96.6% of overall patients (316/327), 96.3% in patients with genotype 1, 97.5% in those with genotype 2, and 95.0% in those with genotype 3. Most of the treatment failures were due to lack of follow-up (3 cases had non-responses, 1 had virological breakthrough, 11 relapsed and 36 did not participate in the follow-up). There was no significant difference in SVR between different genotypes and liver statuses (P < 0.05). Patients with lower alanine aminotransferase levels at baseline who achieved an end of treatment response were more likely to achieve SVR12 (P < 0.05). High SVR was observed regardless of age, gender, liver status, alpha-fetoprotein, HCV RNA levels or history of antiviral therapy (P > 0.05 for all). The cumulative hepatocellular carcinoma occurrence and recurrence rate after using the DAAs was 0.9%. Most of the adverse events were mild. We found two cases of special adverse events. One case involved facial and bilateral lower extremity edema, and the other case showed an interesting change in lipid levels while on medication. No severe adverse events were noted. CONCLUSION The DAA-based regimens tested in this study have excellent effectiveness and safety in all patients infected with HCV genotypes 1, 2 and 3, including those with cirrhosis.
RASSF6 Is Downregulated In Human Bladder Cancers And Regulates Doxorubicin Sensitivity And Mitochondrial Membrane Potential Via The Hippo Signaling Pathway

Background The present study aimed to investigate the clinicopathological significance and biological roles of RASSF6 in human bladder cancers. Materials and methods Immunohistochemistry and Western blots were used to examine the protein expression of RASSF6 in bladder cancer tissues. Biological roles of RASSF6 were examined using MTT, colony formation assay, Matrigel invasion assay, cell cycle analysis, AnnexinV/PI staining and JC-1 staining. Western blot analysis was used to examine the potential mechanism. Results We found that RASSF6 was downregulated in 73 of 138 bladder cancer specimens, which correlated with advanced stages. RASSF6 overexpression decreased the cell growth rate and inhibited invasion ability in T24 cell line. Downregulation of RASSF6 using siRNA increased the cell proliferation rate and promoted invasion in 5637 cell line. Cell cycle studies showed that RASSF6 overexpression suppressed the process of cell cycle progression. RASSF6 overexpression also increased the cellular response to doxorubicin (DOX) treatment. AnnexinV/PI staining showed that RASSF6 overexpression promoted DOX-induced apoptosis with increased cytochrome c and cleavage of caspase-3 and caspase-9. We also showed that RASSF6 overexpression downregulated the mitochondrial membrane potential, while RASSF6 depletion showed the opposite effect. Western blot analysis demonstrated that RASSF6 overexpression repressed p-Rb and Bcl-xL while upregulating p21 expression. In addition, we found that RASSF6 overexpression affected the Hippo signaling pathway by downregulating YAP. Depletion of YAP downregulated Bcl-xL expression and abolished the effect of RASSF6 on Bcl-xL. Depletion of YAP also upregulated the level of apoptosis and downregulated mitochondrial membrane potential. YAP siRNA abolished the effects of RASSF6 on DOX-induced apoptosis and loss of mitochondrial membrane potential. Conclusion Taken together, our results showed that RASSF6 was downregulated in bladder cancers. RASSF6 inhibited cell proliferation and invasion, as well as the progression of cancer, by regulating DOX sensitivity and mitochondrial membrane potential, possibly via the Hippo signaling pathway.