Miracle-dz/UniFAR-FTUs huggingface dataset:
18F-FDG PET/CT longitudinal studies in patients with advanced metastatic melanoma for response evaluation of combination treatment with vemurafenib and ipilimumab

Sixteen BRAF-mutation positive, metastatic melanoma patients with highly advanced disease received combination therapy of vemurafenib and ipilimumab as an individual treatment decision. Our aim was to assess the role of fluorine-18-fluorodeoxyglucose (18F-FDG) PET/computed tomography (PET/CT) in the evaluation of the clinical benefit (CB) of this combination treatment. After clinical improvement under vemurafenib monotherapy, four cycles of ipilimumab were additionally administered. 18F-FDG PET/CT was performed before the start, after two cycles and after completion of the combined ipilimumab/vemurafenib treatment. PET-based patient response evaluation to treatment was based on the European Organization for Research and Treatment of Cancer and the PET Response Evaluation Criteria for Immunotherapy criteria. Progression-free survival (PFS) from the end of combination treatment was calculated. According to their best clinical response at the end of combination treatment, eight patients showed CB and eight patients had no-CB. Two patients revealed extraordinary good clinical outcome with PFS of more than 5 years. Overall, 13 out of 16 patients were correctly classified by the European Organization for Research and Treatment of Cancer and 15 out of 16 by the PET Response Evaluation Criteria for Immunotherapy criteria. Median PFS was 8.8 months among PET-responders and 3.6 months among nonresponders. During immunotherapy administration seven patients developed radiologic signs of immune-related adverse events (irAEs), with colitis and arthritis being the most frequent ones; these patients had a significantly longer PFS than those without irAEs (P=0.036). 18F-FDG PET/CT is a valuable tool for the evaluation of patients receiving a combination of targeted treatment and immunotherapy. The appearance of irAEs on PET/CT might correlate with benefit to immunotherapy.
Amniotic Membrane Transplantation in Strabismus Surgery

ABSTRACT Purpose: Adhesions between the extraocular muscles and surrounding tissues pose a main cause of failure of strabismus reoperations. Amniotic membrane (AM) transplantation during extraocular muscle surgery, to prevent the formation of adhesions, has been a subject of research during the past decade. This review aims to determine the value, indications, and tips on usage of AM transplantation during strabismus surgery. Materials and methods: All references cited in PubMed in English were searched using the key words: amniotic membrane strabismus or amniotic membrane extraocular muscles, and a brief summary of these was described. In addition, certain articles were chosen to provide introductory information on wound healing and fibrosis, AM properties and how it works after transplantation, and AM processing and preservation. Results: AM used for transplantation during extraocular muscle surgery may be cryopreserved, dried, or fresh. It may be oriented with its stroma or epithelium towards the muscle. It may or may not be fixed with sutures. What were the best choices? Various studies attempted to answer these questions. Many of the studies reviewed, however, were inconclusive or contradictory. Fresh AM seemed effective, but carried a risk of transmission of communicable diseases. Dried membrane was not of value in preventing adhesions. Histopathologically, cryopreserved membrane prevented the development of adhesions in the region of its presence, regardless of its orientation, and without the need for suture fixation. To accentuate this histopathological effect during clinical practice, it was recommended to utilize the largest segment possible of cryopreserved membrane and limit its usage to cases where adhesions are expected to be the main cause of failure of strabismus surgery. Conclusion: Cryopreserved AM transplantation was safe and histopathologically effective in preventing adhesions. This effect was, however, less pronounced clinically. Its use during strabismus reoperations is merited if previous recommendations and precautions are considered.
Quadriceps Impairment Is Associated with Gait Mechanics in Young Adults with Obesity

Purpose Obesity influences gait and muscle function, which may contribute to knee osteoarthritis. This study aimed 1) to compare gait biomechanics and quadriceps function between individuals with and without obesity and 2) to examine the association between quadriceps function and gait biomechanics. Methods Forty-eight individuals with and 48 without obesity participated and were matched on age and sex. Gait biomechanics at standardized and self-selected speeds were used to assess peak vertical ground reaction force (vGRF), vertical loading rate (vLR), internal knee extension moment (KEM), peak knee flexion angle (KFA), knee flexion excursion (KFE), and knee joint stiffness. Quadriceps function was assessed using peak isometric strength (peak torque), early (RTD100) and late (RTD200) rate of torque development (RTD), and vastus lateralis cross-sectional area (CSA) and echo intensity (EI). Results When normalized to fat-free mass, individuals with obesity had lower RTD100 (P = 0.04) and RTD200 (P = 0.02) but higher vastus lateralis CSA (P < 0.01) and EI (P < 0.01) compared with normal weight controls. The group–speed interaction was significant for normalized vGRF (P < 0.01), normalized vLR (P = 0.02), normalized KEM (P = 0.03), and normalized knee joint stiffness (P = 0.02). Post hoc analyses indicate a smaller normalized vGRF and normalized KEM, and lower knee joint stiffness in individuals with obesity compared with normal weight controls at self-selected speed. There were main effects of speed for all kinematic and kinetic variables, and body mass index group for all absolute kinetic variables as well as normalized vGRF (all P < 0.001). A lower vastus lateralis EI (P = 0.04) and greater RTD100 (P < 0.01) were associated with a larger KEM in individuals with obesity. Conclusion Individuals with obesity have quadriceps dysfunction that is weakly associated with KEM during walking. Exercise interventions that improve quadriceps function may improve walking mechanics.
Poisson Multilevel Models with Small Samples

Abstract Recent methodological studies have investigated the properties of multilevel models with small samples. Previous work has primarily focused on continuous outcomes and little attention has been paid to count outcomes. The estimation of count outcome models can be difficult because the likelihood has no closed-form solution, meaning that approximation methods are required. Although adaptive Gaussian quadrature (AGQ) is generally seen as the gold standard, its comparative performance has been investigated with larger samples. AGQ approximates the full likelihood, a function that is known to produce biased estimates with small samples with continuous outcomes. Conversely, penalized quasi-likelihood (PQL) is considered to be a less desirable approximation; however, it can approximate the restricted likelihood function, a function that is known to perform well with smaller samples with continuous outcomes. The goal of this paper is to compare the small sample bias of full likelihood methods to the linearization bias of PQL with restricted likelihood. Simulation results indicate that the linearization bias of PQL is preferable to the finite sample bias of AGQ with smaller samples.
Stored red blood cells enhance in vivo migration of dendritic cells by promoting reactive oxygen species–induced cytoskeletal rearrangement

A complex array of physicochemical changes occurs in red blood cells (RBCs) during storage, leading to enhanced posttransfusion clearance. Dendritic cells (DCs) play crucial roles in the engulfment of aged RBCs; however, it is unclear how stored RBCs (sRBCs) modulate their responses to inflammatory stimuli and DC migration ability.
Identification of the Chemical Constituents of an Anti-Arthritic Chinese Medicine Wen Luo Yin by Liquid Chromatography Coupled with Mass Spectrometry

Wen Luo Yin (WLY), a well-known traditional Chinese medicine formulation, has been used as a complementary therapy for the treatment of rheumatoid arthritis in clinical settings. However, the chemical constituents of WLY remain unclear. In this study, a high-performance liquid chromatography coupled with tandem mass spectrometry method was established to separate and comprehensively identify the chemical constituents of WLY. The analytes were eluted with a mobile phase of acetonitrile and 0.1% aqueous acetic acid. Mass detection was performed in both positive and negative ion mode. The MS/MS fragmentation pathways were proposed for the identification of the components. A total of 42 compounds including sesquiterpenes, alkaloids, biflavonoids, polyacetylenes, phenylpropanoids and acetylenic phenols were identified unambiguously or tentatively according to their retention times and mass behavior with those of authentic standards or literature data. The identification and structural elucidation of chemical constituents may provide important information for quality control and pharmacological research of WLY.
The Developmental Sequence and Relations Between Gesture and Spoken Language in Toddlers With Autism Spectrum Disorder.

In typical development, gestures precede and predict language development. This study examines the developmental sequence of expressive communication and relations between specific gestural and language milestones in toddlers with autism spectrum disorder (ASD), who demonstrate marked difficulty with gesture production and language. Communication skills across five stages (gestures, word approximations, first words, gesture-word combinations, and two-word combinations) were assessed monthly by blind raters for toddlers with ASD participating in an randomized control trial of parent-mediated treatment (N = 42, 12-30 months). Findings revealed that toddlers acquired skills following a reliable (vs. idiosyncratic) sequence and the majority of toddlers combined gestures with words before combining words in speech, but in contrast to the pattern observed in typical development, a significant subset acquired pointing after first words.
Increased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathies

Neuropathic pain is a significant public health challenge, yet the underlying mechanisms remain poorly understood. Painful small fiber neuropathy (SFN) may be caused by gain-of-function mutations in Nav1.8, a sodium channel subtype predominantly expressed in peripheral nociceptive neurons. However, it is not clear how Nav1.8 disease mutations induce sensory neuron hyperexcitability. Here we studied two mutations in Nav1.8 associated with hypersensitive sensory neurons: G1662S reported in painful SFN; and T790A, which underlies increased pain behaviors in the Possum transgenic mouse strain. We show that, in male DRG neurons, these mutations, which impair inactivation, significantly increase TTX-resistant resurgent sodium currents mediated by Nav1.8. The G1662S mutation doubled resurgent currents, and the T790A mutation increased them fourfold. These unusual currents are typically evoked during the repolarization phase of action potentials. We show that the T790A mutation greatly enhances DRG neuron excitability by reducing current threshold and increasing firing frequency. Interestingly, the mutation endows DRG neurons with multiple early afterdepolarizations and leads to substantial prolongation of action potential duration. In DRG neurons, siRNA knockdown of sodium channel β4 subunits fails to significantly alter T790A current density but reduces TTX-resistant resurgent currents by 56%. Furthermore, DRG neurons expressing T790A channels exhibited reduced excitability with fewer early afterdepolarizations and narrower action potentials after β4 knockdown. Together, our data demonstrate that open-channel block of TTX-resistant currents, enhanced by gain-of-function mutations in Nav1.8, can make major contributions to the hyperexcitability of nociceptive neurons, likely leading to altered sensory phenotypes including neuropathic pain in SFN. SIGNIFICANCE STATEMENT This work demonstrates that two disease mutations in the voltage-gated sodium channel Nav1.8 that induce nociceptor hyperexcitability increase resurgent currents. Nav1.8 is crucial for pain sensations. Because resurgent currents are evoked during action potential repolarization, they can be crucial regulators of action potential activity. Our data indicate that increased Nav1.8 resurgent currents in DRG neurons greatly prolong action potential duration and enhance repetitive firing. We propose that Nav1.8 open-channel block is a major factor in Nav1.8-associated pain mechanisms and that targeting the molecular mechanism underlying these unique resurgent currents represents a novel therapeutic target for the treatment of aberrant pain sensations.
Epidemiological Aspects of Renal Impairment in Patients with Type 2 Diabetes

Diabetes is a leading cause of renal impairment (RI) and indication of the need for renal replacement therapy in many parts of the world. Albuminuria and RI are the two main forms of diabetic kidney disease. The overall aims of this thesis were to explore risk factors and consequences associated with albuminuria and RI in patients with type 2 diabetes (T2D), as well as to assess the relationship between blood pressure variables, cardiovascular events and all-cause mortality. The studies were based on data from the Swedish National Diabetes Register (NDR). Study I followed 3,367 patients with T2D who did not exhibit signs of albuminuria or RI from 2002 to 2007 in order to evaluate the risk of developing them. A total of 20% of patients developed albuminuria and 11% developed RI. Among those with one of the two conditions, 62% had normoalbuminuric RI. Development of albuminuria or RI was independently associated with advanced older age, high systolic blood pressure and elevated triglycerides. The independent risk factors were obesity, poor glycemic control, smoking, low HDLcholesterol and male gender for developing albuminuria, as opposed to elevated plasma creatinine at baseline and female gender for developing RI. Different sets of risk factors were associated with development of RI and albuminuria. High body mass index (BMI) was an independent risk factor for RI when renal function was calculated with the MDRD equation, while low BMI was a risk factor with when the Cockcroft-Gault equation was used. In other words, the equation chosen to estimate renal function is important when
The Relationship among EFL Reading, Vocabulary Knowledge and Grammar Knowledge : In Terms of Threshold Hypothesis

Some researchers (e.g., Alderson, 1984; Nation & Coady, 1988; Laufer, 1992; Haynes, 1993) have shown the intimate relationship between L2/FL vocabulary knowledge and L2/FL reading. On the other hand, other researchers suggest that grammar knowledge plays an important role in L2/FL reading. Leaver, Ehrman & Shekhtman (2005) and Grabe & Fredricka (2011) assert that to be able to read well, we need to know a lot of words, and that we also need to know the grammatical rules. In this paper, we will examine the relationship among EFL reading, vocabulary knowledge and grammar knowledge in terms of the threshold hypothesis.
Metformin Regulates Key MicroRNAs to Improve Endometrial Receptivity Through Increasing Implantation Marker Gene Expression in Patients with PCOS Undergoing IVF/ICSI

To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not well-known. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (non-metformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR-1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group (P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics (P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics (P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women.
Individual differences in response precision correlate with adaptation bias

The internal representation of stimuli is imperfect and subject to bias. Noise introduced at initial encoding and during maintenance degrades the precision of representation. Stimulus estimation is also biased away from recently encountered stimuli, a phenomenon known as adaptation. Within a Bayesian framework, greater biases are predicted to result from poor precision. We tested for this effect in individual difference measures. 202 subjects contributed data through an on-line experiment (https://cfn.upenn.edu/iadapt). During separate face and color blocks, subjects performed three different tasks: an immediate stimulus-match (15 trials), a 5 seconds delayed match (30 trials), and 5 seconds of adaptation followed by a delayed match (30 trials). The stimulus spaces were circular and subjects entered their responses using a color/face wheel. Bias and precision of responses were extracted by fitting a mixture of von Mises distributions to account for random guesses. Two blocks of each measure were obtained, allowing for tests of measure reliability. We found that reliable differences between individuals in precision were as great as those between tasks or materials. The adaptation manipulation induced the expected bias in responses (colors: 7.8°; faces: 5.0°), and the magnitude of this bias reliably and substantially varied between subjects. Across subjects, there was a negative correlation between mean precision and bias (color: ρ = −0.26; faces: ρ = −0.13). This relationship was replicated in a new experiment with 192 subjects (color: ρ = −0.22; faces: ρ = −0.19). This result is consistent with a Bayesian observer model, in which individual differences in the precision of perceptual representation influences the magnitude of adaptation bias.
p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75NTR) signaling. The p75NTR is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75NTR on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii (T. gondii) infection‐induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75NTR upon infection in wild‐type mice. Although cell recruitment and phagocytic capacity of p75NTRexonIV knockout (p75−/−) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75−/− mice upregulated the production of the cytokines interleukin (IL)‐10, IL‐6 as well as IL‐1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75NTR, were highly increased upon chronic infection in the brain of wild‐type and p75−/− mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation‐induced changes in spine density were rescued in the p75−/− mice. In conclusion, these findings indicate that neurotrophin signaling via the p75NTR affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.
Predicting VTE in Cancer Patients: Candidate Biomarkers and Risk Assessment Models

Risk prediction of chemotherapy-associated venous thromboembolism (VTE) is a compelling challenge in contemporary oncology, as VTE may result in treatment delays, impaired quality of life, and increased mortality. Current guidelines do not recommend thromboprophylaxis for primary prevention, but assessment of the patient’s individual risk of VTE prior to chemotherapy is generally advocated. In recent years, efforts have been devoted to building accurate predictive tools for VTE risk assessment in cancer patients. This review focuses on candidate biomarkers and prediction models currently under investigation, considering their advantages and disadvantages, and discussing their diagnostic performance and potential pitfalls.
Decreased phototoxicity of photodynamic therapy by Cx32/Cx26‐composed GJIC: A “Good Samaritan” effect

Photodynamic therapy (PDT) has been widely used to treat malignant tumors. Our previous studies indicated that connexin (Cx) 32‐ and Cx26‐composed gap junctional intercellular communication (GJIC) could improve the phototoxicity of PDT. However, the role of heterotypic Cx32/Cx26‐formed GJIC in PDT phototoxicity is still unknown. Thus, the present study was aimed to investigate the effect of Cx32/Cx26‐formed GJIC on PDT efficacy.
Does survival context enhance memory for source? A within-subjects comparison

ABSTRACT Nairne, Thompson, and Pandeirada [2007. Adaptive memory: Survival processing enhances retention. Journal of Experimental Psychology: Learning, Memory, and Cognition, 33, 263–273] demonstrated that processing words according to their relevance to a survival scenario enhanced their subsequent retrieval in recall and recognition tasks compared to a variety of control scenarios. From an adaptive perspective, it is maintained that processing words in a survival context should also enhance memory for source; however, evidence in the literature is rather mixed regarding a survival context advantage for source memory. In the current study, we conducted four experiments to systematically investigate the survival advantage in source memory, when the context itself is the source, with both recall (Experiments 1A and 1B) and recognition tests (Experiments 2A and 2B). Results showed a survival advantage for item memory over the control contexts in all experiments. The survival context advantage was not extended to source memory performance in Experiment 1A. Results from all other experiments, however, indicated a survival context advantage for both item and source memory. Findings are discussed in relation to possible proximate mechanisms underlying the survival processing effect.