Takshan/R1 huggingface dataset:
Molecular Defects of the Disease-Causing Human Arrestin-1 C147F Mutant.

Purpose: The purpose of this study was to identify the molecular defect in the disease-causing human arrestin-1 C147F mutant. Methods: The binding of wild-type (WT) human arrestin-1 and several mutants with substitutions in position 147 (including C147F, which causes dominant retinitis pigmentosa in humans) to phosphorylated and unphosphorylated light-activated rhodopsin was determined. Thermal stability of WT and mutant human arrestin-1, as well as unfolded protein response in 661W cells, were also evaluated. Results: WT human arrestin-1 was selective for phosphorylated light-activated rhodopsin. Substitutions of Cys-147 with smaller side chain residues, Ala or Val, did not substantially affect binding selectivity, whereas residues with bulky side chains in the position 147 (Ile, Leu, and disease-causing Phe) greatly increased the binding to unphosphorylated rhodopsin. Functional survival of mutant proteins with bulky substitutions at physiological and elevated temperature was also compromised. C147F mutant induced unfolded protein response in cultured cells. Conclusions: Bulky Phe substitution of Cys-147 in human arrestin-1 likely causes rod degeneration due to reduced stability of the protein, which induces unfolded protein response in expressing cells.
Seasonality in trauma admissions - Are daylight and weather variables better predictors than general cyclic effects?

BACKGROUND: Trauma is a leading global cause of death, and predicting the burden of trauma admissions is vital for good planning of trauma care. Seasonality in trauma admissions has been found in several studies. Seasonal fluctuations in daylight hours, temperature and weather affect social and cultural practices but also individual neuroendocrine rhythms that may ultimately modify behaviour and potentially predispose to trauma. The aim of the present study was to explore to what extent the observed seasonality in daily trauma admissions could be explained by changes in daylight and weather variables throughout the year. METHODS: Retrospective registry study on trauma admissions in the 10-year period 2001-2010 at Oslo University Hospital, Ullevål, Norway, where the amount of daylight varies from less than 6 hours to almost 19 hours per day throughout the year. Daily number of admissions was analysed by fitting non-linear Poisson time series regression models, simultaneously adjusting for several layers of temporal patterns, including a non-linear long-term trend and both seasonal and weekly cyclic effects. Five daylight and weather variables were explored, including hours of daylight and amount of precipitation. Models were compared using Akaike's Information Criterion (AIC). RESULTS: A regression model including daylight and weather variables significantly outperformed a traditional seasonality model in terms of AIC. A cyclic week effect was significant in all models. CONCLUSION: Daylight and weather variables are better predictors of seasonality in daily trauma admissions than mere information on day-of-year.
Repeated in-field radiosurgery for locally recurrent brain metastases: Feasibility, results and survival in a heavily treated patient cohort.

PURPOSE: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS. METHODS: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed. RESULTS: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1-37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12-28 Gy) in 1-5 fractions to the median 69% isodose (range, 53-80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities. CONCLUSIONS: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Functional analysis of a pathogenesis-related thaumatin-like protein gene TaLr35PR5 from wheat induced by leaf rust fungus.

BACKGROUND: Plants have evolved multifaceted defence mechanisms to resist pathogen infection. Production of the pathogenesis-related (PR) proteins in response to pathogen attack has been implicated in plant disease resistance specialized in systemic-acquired resistance (SAR). Our earlier studies have reported that a full length TaLr35PR5 gene, encoding a protein exhibiting amino acid and structural similarity to a sweet protein thaumatin, was isolated from wheat near-isogenic line TcLr35. The present study aims to understand the function of TaLr35PR5 gene in Lr35-mediated adult resistance to Puccinia triticina. RESULTS: We determined that the TaLr35PR5 protein contained a functional secretion peptide by utilizing the yeast signal sequence trap system. Using a heterologous expression assay on onion epidermal cells we found that TaLr35PR5 protein was secreted into the apoplast of onion cell. Expression of TaLr35PR5 was significantly reduced in BSMV-induced gene silenced wheat plants, and pathology test on these silenced plants revealed that Lr35-mediated resistance phenotype was obviously altered, indicating that Lr35-mediated resistance was compromised. CONCLUSIONS: All these findings strongly suggest that TaLr35PR5 is involved in Lr35-mediated adult wheat defense in response to leaf rust attack.
Added value of diffusion-weighted imaging in hepatic tumors and its impact on patient management.

BACKGROUND: To investigate the added diagnostic value of diffusion-weighted imaging (DWI) of the liver and its impact on therapy decisions in patients with hepatic malignancy. METHODS: Interdisciplinary gastrointestinal tumorboard cases concerning patients with hepatic malignancies discussed between 11/2015 and 06/2016 were included in this retrospective, single-center study. Two radiologists independently reviewed the respective liver MR-examination first without, then with DWI. The readers were blinded regarding number, position and size of hepatic malignancies. Cases in which DWI revealed additional findings concerning the hepatic tumor status as compared to conventional sequences alone were presented to experienced members of the interdisciplinary tumor board. In this retrospective setting changes in treatment decisions based on these additional findings in the DWI sequences were recorded. RESULTS: A total of 87 patients were included. DWI revealed additional findings in 12 patients (13,8%). These new findings had a direct effect on the therapy in 8 patients (9,2%): In 6 patients (6,9%) the surgical/interventional treatment was adapted (n = 5: extended resection, n = 1: with transarterial chemoembolization of a single hepatocellular carcinoma only detectable in DWI); 2 patients (2,3%) received systemic therapy (n = 1: neo-adjuvant, n = 1: palliative) based on the additional findings in DWI. In 4 patients (4.6%) additional DWI findings did not affect the therapeutic decision. CONCLUSIONS: DWI is a relevant diagnostic tool in oncologic imaging of the liver. By providing further information regarding tumor load in hepatic malignancies it can lead to a significant change in treatment.
Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.

BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.
Dual antitumour effect of 5-azacytidine by inducing a breakdown of resistance-mediating factors and epigenetic modulation.

BACKGROUND: The cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown promising anticancer activity in early clinical settings by selectively inducing apoptosis in different tumour types. However, some tumour entities such as hepatocellular carcinoma (HCC) display an inherent resistance to TRAIL. A huge effort has been made to unravel strategies for a clinically applicable sensitisation of resistant cancer cells to TRAIL. Reversible epigenetic alterations such as DNA methylation play a major role in development, maintenance and resistance phenomena of tumour cells. Currently, several clinical trials are exploiting the potential of epigenetic drugs, such as 5-azacytidine (5-aza-CR) or 5-aza-2'-deoxycytidine (5-aza-dC) to break primary or secondary resistance phenomena of cancer cells. Therefore, 5-aza-CR and 5-aza-dC were investigated in the context of TRAIL resistance. METHODS: Alterations in proliferation, apoptosis, regulatory proteins and toxicity were investigated in TRAIL-resistant hepatoma, and also in renal, colon and pancreatic cancer cells as well as non-transformed human-derived primary hepatocytes, tissue slices isolated from human liver and non-malignant colon cells, all of which had been exposed to demethylating drugs and/or TRAIL. RESULTS: Within hours, 5-aza-CR but not 5-aza-dC sensitised in vitro cultured tumour cells to TRAIL, first by activating caspases, followed by a subsequent induction of apoptosis. This surprisingly rapid sensitisation was confirmed in vivo employing a chorioallantoic membrane assay. As a major mechanism, a 5-aza-CR-induced inhibition of cellular protein synthesis was found which led to a breakdown of tumour-protecting factors such as the antiapoptotic factor FLICE inhibitory protein (FLIP). Importantly, TRAIL and 5-aza-CR did not induce relevant toxicity or apoptosis in primary hepatocytes, liver slices from different human donors and in normal colon cells. CONCLUSIONS: Molecular evidence is provided for a novel 5-aza-CR-based translational approach enabling a twofold treatment of apoptosis-resistant tumour entities, not only by an epigenetic reversion of the malignancy-associated phenotype but also by an efficient resensitization to apoptosis-inducing substances such as TRAIL.
ABO, Rhesus, and Kell Antigens, Alleles, and Haplotypes in West Bengal, India.

Background: Few studies have documented the blood group antigens in the population of eastern India. Frequencies of some common alleles and haplotypes were unknown. We describe phenotype, allele, and haplotype frequencies in the state of West Bengal, India. Methods: We tested 1,528 blood donors at the Medical College Hospital, Kolkata. The common antigens of the ABO, Rhesus, and Kell blood group systems were determined by standard serologic methods in tubes. Allele and haplotype frequencies were calculated with an iterative method that yielded maximum-likelihood estimates under the assumption of a Hardy-Weinberg equilibrium. Results: The prevalence of ABO antigens were B (34%), O (32%), A (25%), and AB (9%) with ABO allele frequencies for O = 0.567, A = 0.189, and B = 0.244. The D antigen (RH1) was observed in 96.6% of the blood donors with RH haplotype frequencies, such as for CDe = 0.688809, cde = 0.16983 and CdE = 0.000654. The K antigen (K1) was observed in 12 donors (0.79%) with KEL allele frequencies for K = 0.004 and k = 0.996. Conclusions: For the Bengali population living in the south of West Bengal, we established the frequencies of the major clinically relevant antigens in the ABO, Rhesus, and Kell blood group systems and derived estimates for the underlying ABO and KEL alleles and RH haplotypes. Such blood donor screening will improve the availability of compatible red cell units for transfusion. Our approach using widely available routine methods can readily be applied in other regions, where the sufficient supply of blood typed for the Rh and K antigens is lacking.
Transfusion strategy for weak D Type 4.0 based on RHD alleles and RH haplotypes in Tunisia.

BACKGROUND: With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D Type 4.0 alleles, occurring in one of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D Type 4.0 in Tunisia. STUDY DESIGN AND METHODS: Donors were randomly screened for the serologic weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single-nucleotide positions. RESULTS: We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D Type 4 allele: 53 weak D Type 4.0, six weak D Type 4.2.2 (DAR), and one weak D Type 4.1. An additional four donors had one variant allele each: DVII, weak D Type 1, weak D Type 3, and weak D type 100, while three donors showed a normal RHD sequence. The weak D Type 4.0 was most often linked to RHCE*ceVS.04.01, weak D Type 4.2.2 to RHCE*ceAR, and weak D Type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles. CONCLUSIONS: Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D Type 4 cluster, of which 88% represented the weak D Type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D+ transfusions for patients with weak D Type 4.0 in Tunisia.
Weak D alleles express distinct phenotypes.

The weak D phenotype is caused by many different RHD alleles encoding aberrant RhD proteins, raising the possibility of distinct serologic phenotypes and of anti-D immunizations in weak D. We reported 6 new RHD alleles, D category III type IV, DIM, and the weak D types 4.1, 4.2.1, 4.2.2, and 17. The immunohematologic features of 18 weak D types were examined by agglutination and flow cytometry with more than 50 monoclonal anti-D. The agglutination patterns of the partial D phenotypes DIM, D(III) type IV, and D(IV) type III correlated well with the D epitope models, those of the weak D types showed no correlation. In flow cytometry, the weak D types displayed type-specific antigen densities between 70 and 4000 RhD antigens per cell and qualitatively distinct D antigens. A Rhesus D similarity index was devised to characterize the extent of qualitative changes in aberrant D antigens and discriminated normal D from all tested partial D, including D category III. In some rare weak D types, the extent of the alterations was comparable to that found in partial Ds that were prone to anti-D immunization. Four of 6 case reports with anti-D in weak D represented auto-anti-D. We concluded that, in contrast to previous assumptions, most weak D types, including prevalent ones, carry altered D antigens. These observations are suggestive of a clinically relevant potential for anti-D immunizations in some, but not in the prevalent weak D types, and were used to derive an improved transfusion strategy in weak D patients. ( Blood. 2000;95:2699-2708)
RHD positive haplotypes in D negative Europeans.

BACKGROUND: Blood group genotyping is increasingly utilized for prenatal diagnosis and after recent transfusions, but still lacks the specificity of serology. In whites, the presence of antigen D is predicted, if two or more properly selected RHD-specific polymorphism are detected. This prediction must fail, if an antigen D negative RHD positive allele is encountered. Excluding RHDpsi and CdeS frequent only in individuals of African descent, most of these alleles are unknown and the population frequency of any such allele has not been determined. METHODS: We screened 8,442 antigen D negative blood donations by RHD PCR-SSP. RHD PCR positive samples were further characterized by RHD exon specific PCR-SSP or sequencing. The phenotype of the identified alleles was checked and their frequencies in Germans were determined. RESULTS: We detected 50 RHD positive samples. Fifteen samples harbored one of three new Del alleles. Thirty samples were due to 14 different D negative alleles, only 5 of which were previously known. Nine of the 14 alleles may have been generated by gene conversion in cis, for which we proposed a mechanism triggered by hairpin formation of chromosomal DNA. The cumulative population frequency of the 14 D negative alleles was 1:1,500. Five samples represented a D+/- chimera, a weak D and three partial D, which had been missed by routine serology; two recipients transfused with blood of the D+/- chimera donor became anti-D immunized. CONCLUSION: The results of this study allowed to devise an improved RHD genotyping strategy, the false-positive rate of which was lower than 1:10,000. The number of characterized RHD positive antigen D negative and Del alleles was more than doubled and their population frequencies in Europe were defined.
How I manage donors and patients with a weak D phenotype.

PURPOSE OF REVIEW: Since the adoption of molecular blood-group typing, the considerable heterogeneity of the serologic entities weak D and DEL at the molecular level has come to light. I offer an approach to the management of donors and patients expressing D antigen weakly and carrying any of the various molecular types of weak D and DEL. RECENT FINDINGS: More than 50 distinct weak D alleles have been described. An internet-based survey of anti-D immunizations occurring in D-positive transfusion recipients reveals that no allo-anti-D has been observed in patients carrying prevalent weak D types. Allo-immunizations are documented for weak D types 4.2 (also known as DAR), 11 and 15. Anti-D immunizations have been reported in D-negative persons transfused with weak D and DEL red blood cells. SUMMARY: Patients carrying any of the prevalent weak D types 1, 2, 3 or 4.1 are not prone to allo-anti-D immunization and may safely be transfused with D-positive red blood cells. Pregnant women with these weak D types need not receive RhIg. We should pay attention to weak D- or DEL-positive blood units that are labelled D-negative. The clinical benefit of removing DEL blood units from our supply of D-negative red blood cell units should be determined.
Dysphagia risk, low muscle strength and poor cognition predict malnutrition risk in older adults athospital admission.

BACKGROUND: Malnutrition in patients admitted to hospital may have detrimental effects on recovery and healing. Malnutrition is preceded by a state of malnutrition risk, yet malnutrition risk is often not detected during admission. The aim of the current study was to investigate the magnitude and potential predictors of malnutrition risk in older adults, at hospital admission. METHODS: A cross-sectional was study conducted in 234 older adults (age ≥ 65 or ≥ 55 for Māori or Pacific ethnicity) at admission to hospital in Auckland, New Zealand. Assessment of malnutrition risk status was performed using the Mini Nutritional Assessment Short-Form (MNA®-SF), dysphagia risk by the Eating Assessment Tool (EAT-10), muscle strength by hand grip strength and cognitive status by the Montreal Cognitive Assessment (MoCA) tool. RESULTS: Among 234 participants, mean age 83.6 ± 7.6 years, 46.6% were identified as at malnutrition risk and 26.9% malnourished. After adjusting for age, gender and ethnicity, the study identified [prevalence ratio (95% confidence interval)] high dysphagia risk [EAT-10 score: 0.98 (0.97-0.99)], low body mass index [kg/m2: 1.02 (1.02-1.03)], low muscle strength [hand grip strength, kg: 1.01 (1.00-1.02)] and decline in cognition [MoCA score: 1.01 (1.00-1.02)] as significant predictors of malnutrition risk in older adults at hospital admission. CONCLUSION: Among older adults recently admitted to the hospital, almost three-quarters were malnourished or at malnutrition risk. As the majority (88%) of participants were admitted from the community, this illustrates the need for routine nutrition screening both at hospital admission and in community-dwelling older adults. Factors such as dysphagia, unintentional weight loss, decline in muscle strength, and poor cognition may indicate increased risk of malnutrition.