Miracle-dz/UniFAR-FTUs huggingface dataset:
Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.

PURPOSE Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti-CTLA-4 and to explore the relationship between autoimmunity and tumor regression. PATIENTS AND METHODS A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status > or = 60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti-CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). RESULTS Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules. CONCLUSION Administration of anti-CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.
Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV

Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells’ functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re‐expression of TRPML1 in neurons. These features were not observed in Niemann–Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV.
Episomal Expression of Truncated Listeriolysin O in LmddA-LLO–E7 Vaccine Enhances Antitumor Efficacy by Preferentially Inducing Expansions of CD4+FoxP3− and CD8+ T Cells

Chen and colleagues developed an improved, attenuated L. monocytogenes–based vaccine that induced the regression of established mouse TC-1 tumors; they show that listeriolysin O serves as a vaccine adjuvant that decreases Treg frequency by inducing the expansion of non-Treg T cells. Studies have shown that Listeria monocytogenes (Lm)–based vaccine expressing a fusion protein comprising truncated listeriolysin O (LLO) and human papilloma virus (HPV) E7 protein (Lm-LLO–E7) induces a decrease in regulatory T cells (Treg) and complete regression of established, transplanted HPV-TC-1 tumors in mice. However, how the Lm-based vaccine causes a decrease in Tregs remains unclear. Using a highly attenuated Lm dal dat ΔactA strain (LmddA)–based vaccine, we report here that the vector LmddA was sufficient to induce a decrease in the proportion of Tregs by preferentially expanding CD4+FoxP3− T cells and CD8+ T cells by a mechanism dependent on and directly mediated by LLO. Episomal expression of a nonhemolytic truncated LLO in Lm (LmddA-LLO) significantly augmented the expansion, thus further decreasing Treg frequency. Although adoptive transfer of Tregs compromised the antitumor efficacy of the LmddA-LLO–E7 vaccine, a combination of LmddA-LLO and an Lm-based vaccine expressing E7 protein (Lm–E7) induced complete regression against established TC-1 tumors. An engineered LLO-minus Lm expressing perfringolysin O (PFO) that enables the recombinant bacteria to exit from the phagolysosome without LLO confirmed that the adjuvant effect was dependent on LLO. These results suggest that LLO may serve as a promising adjuvant by preferentially inducing the expansions of CD4+FoxP3− T cells and CD8+ T cells, thus reducing the ratio of Tregs to CD4+FoxP3− T cells and to CD8+ T cells favoring immune responses to eradicate tumor. Cancer Immunol Res; 2(9); 911–22. ©2014 AACR.
Evidence Aggregation for Answer Re-Ranking in Open-Domain Question Answering

A popular recent approach to answering open-domain questions is to first search for question-related passages and then apply reading comprehension models to extract answers. Existing methods usually extract answers from single passages independently. But some questions require a combination of evidence from across different sources to answer correctly. In this paper, we propose two models which make use of multiple passages to generate their answers. Both use an answer-reranking approach which reorders the answer candidates generated by an existing state-of-the-art QA model. We propose two methods, namely, strength-based re-ranking and coverage-based re-ranking, to make use of the aggregated evidence from different passages to better determine the answer. Our models have achieved state-of-the-art results on three public open-domain QA datasets: Quasar-T, SearchQA and the open-domain version of TriviaQA, with about 8 percentage points of improvement over the former two datasets.
Sharing the Journey: Exploring a Social Leisure Program for Persons with Dementia and Their Spouses

ABSTRACT In this article, we highlight the marginalization and exclusion persons with dementia and their spouses often face in leisure practices and spaces. We then explore aspects of a peer-led community social program aimed at inclusion. Framed in creative analytic practice, the experiences of members of the social program are shared through a composite narrative. This narrative tells the story of a couple from the point of diagnosis who seek support and education and eventually find deep social connections with others who are on a shared journey. We draw from this narrative to explore meanings of inclusion for spousal couples on the dementia journey and use a social justice lens to consider how to address experiences of exclusion in leisure practices and spaces.
Prior Corneal Scarification and Injection of Immune Serum are Not Required Before Ocular HSV-1 Infection for UV-B-Induced Virus Reactivation and Recurrent Herpetic Corneal Disease in Latently Infected Mice

Abstract Purpose: Blinding ocular herpetic disease in humans is due to spontaneous reactivation of herpes simplex virus type 1 (HSV-1) from latency, rather than to primary acute infection. Mice latently infected with HSV-1 undergo little or no in vivo spontaneous reactivation with accompanying virus shedding in tears. HSV-1 reactivation can be induced in latently infected mice by several in vivo procedures, with UV-B-induced reactivation being one commonly used method. In the UV-B model, corneas are scarified (lightly scratched) just prior to ocular infection to increase efficiency of the primary infection and immune serum containing HSV-1 neutralizing antibodies is injected intraperitoneally (i.p.) to increase survival and decrease acute corneal damage. Since scarification can significantly alter host gene transcription in the cornea and in the trigeminal ganglia (TG; the site of HSV-1 latency) and since injection of immune serum likely modulates innate and adaptive herpes immunity, we investigated eliminating both treatments. Material and Methods: Mice were infected with HSV-1 with or without corneal scarification and immune serum. HSV-1 reactivation and recurrent disease were induced by UV-B irradiation. Results: When corneal scarification and immune serum were both eliminated, UV-B irradiation still induced both HSV-1 reactivation, as measured by shedding of reactivated virus in tears and herpetic eye disease, albeit at reduced levels compared to the original procedure. Conclusion: Despite the reduced reactivation and disease, avoidance of both corneal scarification and immune serum should improve the clinical relevance of the UV-B mouse model.
Prostate-specific antigen decline pattern in advanced prostate cancer receiving androgen deprivation therapy and relationship with prostate-specific antigen progression

Abstract Introduction: The aim of this study is to evaluate prostate-specific antigen decline pattern including prostate-specific antigen kinetics following androgen deprivation therapy on prostate-specific antigen progression in the patients with advanced prostate cancer. Materials and methods: Ninety-seven advanced prostate cancer patients receiving maximum androgen deprivation therapy were enrolled in case–control study. Baseline prostate-specific antigen, Gleason Score, bone metastase, nadir prostate-specific antigen, time to nadir prostate-specific antigen, declining slope to nadir prostate-specific antigen, estimated baseline prostate-specific antigen half-time, current prostate-specific antigen, post-nadir prostate-specific antigen time, estimated prostate-specific antigen, estimated decline of baseline prostate-specific antigen as quantitative, and ratio were recorded and calculated. Results: The ratio of prostate-specific antigen progression was significantly lower at the patients who had slower declining slope to prostate-specific antigen, longer time to nadir prostate-specific antigen, and lower estimated decline ratio of baseline prostate-specific antigen (p: .016, p: .020, and p: .026, respectively). Conclusions: The shorter time to nadir prostate-specific antigen following androgen deprivation therapy, faster declining slope to nadir prostate-specific antigen and higher estimated decline ratio of baseline prostate-specific antigen are associated with higher risk of disease progression in patients with hormone-sensitive prostate cancer.
Effect of Energy Equalization on the Intelligibility of Speech in Fluctuating Background Interference for Listeners With Hearing Impairment

The masking release (MR; i.e., better speech recognition in fluctuating compared with continuous noise backgrounds) that is evident for listeners with normal hearing (NH) is generally reduced or absent for listeners with sensorineural hearing impairment (HI). In this study, a real-time signal-processing technique was developed to improve MR in listeners with HI and offer insight into the mechanisms influencing the size of MR. This technique compares short-term and long-term estimates of energy, increases the level of short-term segments whose energy is below the average energy, and normalizes the overall energy of the processed signal to be equivalent to that of the original long-term estimate. This signal-processing algorithm was used to create two types of energy-equalized (EEQ) signals: EEQ1, which operated on the wideband speech plus noise signal, and EEQ4, which operated independently on each of four bands with equal logarithmic width. Consonant identification was tested in backgrounds of continuous and various types of fluctuating speech-shaped Gaussian noise including those with both regularly and irregularly spaced temporal fluctuations. Listeners with HI achieved similar scores for EEQ and the original (unprocessed) stimuli in continuous-noise backgrounds, while superior performance was obtained for the EEQ signals in fluctuating background noises that had regular temporal gaps but not for those with irregularly spaced fluctuations. Thus, in noise backgrounds with regularly spaced temporal fluctuations, the energy-normalized signals led to larger values of MR and higher intelligibility than obtained with unprocessed signals.
Classification of prokaryotic genetic replicators: between selfishness and altruism

Prokaryotes harbor a variety of genetic replicators, including plasmids, viruses, and chromosomes, each having different effects on the phenotype of the hosting cell. Here, we propose a classification for replicators of bacteria and archaea on the basis of their horizontal‐transfer potential and the type of relationships (mutualistic, symbiotic, commensal, or parasitic) that they have with the host cell vehicle. Horizontal movement of replicators can be either active or passive, reflecting whether or not the replicator encodes the means to mediate its own transfer from one cell to another. Some replicators also have an infectious extracellular state, thus separating viruses from other mobile elements. From the perspective of the cell vehicle, the different types of replicators form a continuum from genuinely mutualistic to completely parasitic replicators. This classification provides a general framework for dissecting prokaryotic systems into evolutionarily meaningful components.
Metal induction of a Pisolithus albus metallothionein and its potential involvement in heavy metal tolerance during mycorrhizal symbiosis.

Metallothioneins (MTs) are small, cysteine-rich peptides involved in intracellular sequestration of heavy metals in eukaryotes. We examined the role in metal homeostasis and detoxification of an MT from the ectomycorrhizal fungus Pisolithus albus (PaMT1). PaMT1 encodes a 35 amino acid-long polypeptide, with 7 cysteine residues; most of them part of a C-x-C motif found in other known basidiomycete MTs. The expression levels of PaMT1 increased as a function of increased external Cu and Cd concentrations and were higher with Cu than with Cd. Heterologous complementation assays in metal-sensitive yeast mutants indicated that PaMT1 encodes a polypeptide capable of conferring higher tolerance to both Cu and Cd. Eucalyptus tereticornis plantlets colonized with P. albus grown in the presence of Cu and Cd showed better growth compared with those with non-mycorrhizal plants. Higher PaMT1 expression levels were recorded in mycorrhizal plants grown in the presence of Cu and Cd compared with those in control mycorrhizal plants not exposed to heavy metals. These data provide the first evidence to our knowledge that fungal MTs could protect ectomycorrhizal fungi from heavy metal stress and in turn help the plants to establish in metal-contaminated sites.
Local regulation of human breast xenograft models

Breast cancer studies implant human cancer cells under the renal capsule, subcutaneously, or orthotopically and often use estrogen supplementation and immune suppressants (etoposide) in xenograft mouse models. However, cell behavior is significantly impacted by signals from the local microenvironment. Therefore, we investigated how the combinatorial effect of the location of injection and procedural differences affected xenograft characteristics. Patient‐derived breast cancer cells were injected into mouse abdominal or thoracic mammary glands ± estrogen and/or etoposide pretreatment. Abdominal xenografts had increased tumor incidence and volume, and decreased latency (P < 0.001) compared to thoracic tumors. No statistically significant difference in tumor volume was found in abdominal xenografts treated ± estrogen or etoposide; however, etoposide suppressed tumor volume in thoracic xenografts (P < 0.02). The combination of estrogen and etoposide significantly decreased tumor incidence in both sites. In addition, mice treated ± estradiol were injected orthotopically or subcutaneously with well‐characterized breast cancer cell lines (MCF7, ZR75‐1, MDA MB‐231, or MCF10Ca1h). Orthotopic injection increased tumor volume; growth varied with estrogen supplementation. Location also altered methylation status of several breast cancer‐related gene promoters. Lastly, vascularization of orthotopic tumors was significantly enhanced compared to subcutaneous tumors. These data suggest that optimal xenograft success occurs with orthotopic abdominal injections and illustrate molecular details of the compelling influence of the local microenvironment on in vivo models. J. Cell. Physiol. 224: 795–806, 2010. Published 2010 Wiley‐Liss, Inc.
Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder.

An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.
Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril

Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.
Comparative Accuracy of 17 Point-of-Care Glucose Meters

Background: The accuracy of point-of-care blood glucose (BG) meters is important for the detection of dysglycemia, calculation of insulin doses, and the calibration of continuous glucose monitors. The objective of this study was to compare the accuracy of commercially available glucose meters in a challenging laboratory study using samples with a wide range of reference BG and hemoglobin values. Methods: Fresh, discarded blood samples from a hospital STAT laboratory were either used without modification, spiked with a glucose solution, or incubated at 37°C to produce 347 samples with an even distribution across reference BG levels from 20 to 440 mg/dl and hemoglobin values from 9 to 16 g/dl. We measured the BG of each sample with 17 different commercially available glucose meters and the reference method (YSI 2300) at the same time. We determined the mean absolute relative difference (MARD) for each glucose meter, overall and stratified by reference BG and by hemoglobin level. Results: The accuracy of different meters widely, exhibiting a range of MARDs from 5.6% to 20.8%. Accuracy was lower in the hypoglycemic range, but was not consistently lower in samples with anemic blood hemoglobin levels. Conclusions: The accuracy of commercially available glucose meters varies widely. Although the sample mix in this study was much more challenging than those that would be collected under most use conditions, some meters were robust to these challenges and exhibited high accuracy in this setting. These data on relative accuracy and robustness to challenging samples may be useful in informing the choice of a glucose meter.
Insulin Resistance Predicts Cognitive Decline: An 11-Year Follow-up of a Nationally Representative Adult Population Sample

OBJECTIVE The aim of this study was to examine whether insulin resistance, assessed by HOMA of insulin resistance (HOMA-IR), is an independent predictor of cognitive decline. RESEARCH DESIGN AND METHODS The roles of HOMA-IR, fasting insulin and glucose, HbA1c, and hs-CRP as predictors of cognitive performance and its change were evaluated in the Finnish nationwide, population-based Health 2000 Health Examination Survey and its 11-year follow-up, the Health 2011 study (n = 3,695, mean age at baseline 49.3 years, 55.5% women). Categorical verbal fluency, word-list learning, and word-list delayed recall were used as measures of cognitive function. Multivariate linear regression analysis was performed and adjusted for previously reported risk factors for cognitive decline. RESULTS Higher baseline HOMA-IR and fasting insulin levels were independent predictors of poorer verbal fluency performance (P = 0.0002 for both) and of a greater decline in verbal fluency during the follow-up time (P = 0.004 for both). Baseline HOMA-IR and insulin did not predict word-list learning or word-list delayed recall scores. There were no interactions between HOMA-IR and apolipoprotein E ε4 (APOEε4) genotype, hs-CRP, or type 2 diabetes on the cognitive tests. Fasting glucose and hs-CRP levels at baseline were not associated with cognitive functioning. CONCLUSIONS Our results show that higher serum fasting insulin and insulin resistance predict poorer verbal fluency and a steeper decline in verbal fluency during 11 years in a representative sample of an adult population. Prevention and treatment of insulin resistance might help reduce cognitive decline later in life.