Miracle-dz/UniFAR-FTUs huggingface dataset:
Current and emerging pharmacotherapy for chronic spontaneous Urticaria: a focus on non-biological therapeutics

ABSTRACT Introduction Chronic spontaneous urticaria (CSU) refers to urticaria (wheals) or angioedema, which occur for a period of six weeks or longer without an apparent cause. The condition may impair the patient’s quality of life. Areas covered Treatment for CSU is mainly symptomatic. Both AAAAI/ACAAI practice parameters and EAACI/GA2LEN/EDF/WAO guidelines suggest CSU management in a stepwise manner. First-line therapy is with second-generation H1-antihistamines. Treatment should be stepped up along the algorithm if symptoms are not adequately controlled. Increasing the dosage of second-generation H1-antihistamines, with the addition of first-generation H1-antihistamines, H2 antagonist, omalizumab, ciclosporin A, or short-term corticosteroid may be necessary. New medications are being developed to treat refractory CSU. They include spleen tyrosine kinase inhibitor, Bruton tyrosine kinase inhibitor, prostaglandin D2 receptor inhibitor, H4-antihistamine, and other agents. The authors discuss these treatments and provide expert perspectives on the management of CSU. Expert opinion Second-generation H1-antihistamines remain the first-line therapeutic options for the management of CSU. For patients not responding to higher-dose H1-antihistamines, international guidelines recommend the addition of omalizumab. Efficacy and safety data for newer agents are still pending. Large-scale, well-designed, randomized, double-blind, placebo-controlled trials will further provide evidence on the safety profile and efficacy of these agents in patients with CSU.
L-carnitine as primary or adjuvant treatment in infertile patients with varicocele. A systematic review.

BACKGROUND Varicocele has been found to impair the function of the epididymis resulting in subfertility whereas the varicocelectomy can resolve the phenomenon. L-carnitine is regarded as a biomarker for the function of the epididymis and has been found in reduced concentrations in infertile patients of various causes, including infertile men with varicocele. It seems that Lcarnitine and varicocele share clinical significance and the area of research looks promising. OBJECTIVE To identify the role of L-carnitine in the treatment of varicocele. MATERIALS AND METHODS A systematic search was performed in Pubmed/Medline with the terms (L-carnitine) and (varicocele) and (L-carnitine) and (varicocelectomy). Inclusion criteria were studies reported outcomes of L-carnitine administration alone or in duet, as primary or adjuvant treatment to varicocele. Exclusion criteria were non-English language and animal studies. Studies using L-carnitine as part of a panel of therapeutic agents were avoided. RESULTS Only four suitable studies were identified for discussion. In one randomized study, the combination of L-carnitine and cinnoxicam improved semen parameters in patients with non-high-grade varicocele compared to L-carnitine alone and had a favourable effect on pregnancy rates but the effect of grade is unknown. In another study, as an adjuvant treatment to varicocelectomy, L-carnitine showed no clear benefit. Finally, in comparison to surgery, the results are inconclusive; two studies showed some benefit might be expected in low-grade or subclinical varicocele, but surgery appears superior. CONCLUSIONS The evidence regarding the role of L-carnitine as a primary or adjuvant treatment of varicocele is sparse. The pathophysiological significance of L-carnitine implicates a potential role of the molecule in the management of varicocele, but the evidence so far is controversial for any recommendations. L-carnitine might be taken into consideration in selected cases; however, further search is needed in order the optimal role of L-carnitine in infertile patients with varicocele to be clarified.
Milk consumption and childhood anthropometric failure in India: Analysis of a national survey

Abstract Dairy milk has been shown to contribute to child growth in many countries, but the relationship between milk intake and anthropometric outcomes among Indian children has not been studied. The objectives were to describe children aged 6–59 months who consume dairy milk in India and determine if dairy milk consumption was associated with lower odds of stunting, underweight and anthropometric failure among Indian children. This was a cross‐sectional study based on the fourth Indian National Family Health Survey (NFHS‐4), which was a national survey conducted between 2015 and 2016 by the Ministry of Health and Family Welfare. The primary exposure was the consumption of dairy milk within the past day or night. The primary outcomes were stunting (height‐for‐age z score < −2), underweight (weight‐for‐age z score < −2) and the composite index of anthropometric failure (CIAF), which is a combination of weight‐for‐age, weight‐for‐height and height‐for‐age. Multivariable logistic regression models and coarsened exact matching (CEM) were used to determine the relationship between dairy milk and odds ratios of each outcome. Setting was in India. Participants were children (N = 107,639) aged 6–59 months. Children who consumed dairy milk in the past day or night had an odds ratio of 0.95 for underweight (95% CI 0.92–0.98, P = .0005), 0.93 for stunting (95% CI 0.90–0.96, P < .0001) and 0.96 for CIAF (95% CI 0.93–0.99, P = .004), compared with children who did not consume dairy milk after adjusting for relevant covariates. When CEM was used among a subset (n = 28,207), evidence for relationships between dairy milk and anthropometric outcomes was consistent but slightly weaker. Widespread, equitable access to dairy milk among childhood may be part of an effort to lower the risk of anthropometric failure among children in India.
Synthesis of Magnetic Molecularly Imprinted Polymer Sorbents for Isolation of Parabens from Breast Milk

Magnetic molecularly imprinted polymers (MMIPs) are an invaluable asset in the development of many methods in analytical chemistry, particularly sample preparation. Novel adsorbents based on MMIPs are characterized by high selectivity towards a specific analyte due to the presence of a specific cavity on their polymer surface, enabling the lock–key model interactions to occur. In addition, the magnetic core provides superparamagnetic properties that allow rapid separation of the sorbent from the sample solution. Such a combination of imprinted polymers with a magnetic core has an innovative influence on the development of separation techniques. Hence, the present study describes the synthesis of MMIPs with 17β-estradiol used as a template molecule in the production of imprinted polymers. The as-prepared sorbent was used for a sorption/desorption study of five parabens from breast milk samples. The obtained results were characterized by sorption efficiency exceeding 92%, which shows the high affinity of the analytes to the functional groups on the sorbent. The final determination of the selected analytes was done with high-performance liquid chromatography using a fluorometric detector. The determined linearity ranges for selected parabens were characterized by high determination coefficients (r2 from 0.9992 to 0.9999), and the calculated limit of detection (LOD) and limit of quantification (LOQ) for the identified compounds were low (LOD from 1.1–2.7 ng mL−1; LOQ from 3.6–8.1 ng mL−1), which makes their quantitative analysis in real samples feasible.
Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Simple Summary The identification of new pharmacological combinations with synergistic effect in multiple myeloma is highly relevant since this is, for the moment, an incurable disease. The high expression of Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases, especially PIM2, in myeloma cells is in agreement with the antiproliferative effect previously shown by the pan-PIM kinase inhibitor PIM447 in these types of cells. Therefore, PIM447 is a good candidate to be studied in new combinations with standard-of-care drugs. In this work, we demonstrate by preclinical studies that PIM447 in combination with the standard treatment pomalidomide + dexamethasone exerts a potent antitumor effect and significantly improves survival with respect to the standard treatment. Our data suggest that these effects are in part mediated by the inhibition of protein translation promoted by this triple combination. These results could be the basis for new clinical trials based on this all-oral combination, which would benefit MM patients. Abstract Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.
Heterosis and combining ability in relation to cytoplasmic diversity in pearl millet

In pearl millet (Pennisetum glaucum) several sources of cytoplasmic male-sterility (CMS) are available. This investigation was undertaken to study the combining ability of alloplasmic isonuclear lines and to quantify the magnitude of heterosis in hybrids based on different CMS sources. Such information is ultimately helpful in determining the relative chances of success with any CMS source. The lines with A3 and A4 cytoplasms were significantly better general combiner for grain yield than the lines retaining either Al male-sterile or fertile cytoplasm. Pollinators IPC 1173, IPC 1600, IPC 1546 and IPC 390 proved their utility for breeding high yielding hybrids. None of the pollinateitS proved to be good combiner simultaneously for all traits. Magnitude of heterosis varied considerably within the hybrids retaining particular cytoplasm. Heterosis was negative for days to flower and of the similar magnitude in the hybrids grouped by their cytoplasmic source. Manifestation of cytoplasmic effects was higher for heterosis for grain yield and plant height than heterosis for days to flower and panicle length. The usefulness of A4 CMS source is discussed, in the light of results obtained here and those already available, in pearl millet hybrid breeding programmes.
Cross verification of independent dose recalculation, log files based, and phantom measurement‐based pretreatment quality assurance for volumetric modulated arc therapy

Abstract Independent treatment planning system (TPS) check with Mobius3D software, log files based quality assurance (QA) with MobiusFX, and phantom measurement‐based QA with ArcCHECK were performed and cross verified for head‐and‐neck (17 patients), chest (16 patients), and abdominal (19 patients) cancer patients who underwent volumetric modulated arc therapy (VMAT). Dosimetric differences and percentage gamma passing rates (%GPs) were evaluated and compared for this cross verification. For the dosimetric differences in planning target volume (PTV) coverage, there was no significant difference among TPS vs. Mobius3D, TPS vs. MobiusFX, and TPS vs. ArcCHECK. For the dosimetric differences in organs at risks (OARs), the number of metrics with an average dosimetric differences higher than ±3% for TPS vs Mobius3D, TPS vs MobiusFX, and TPS vs ArcCHECK were 1, 1, 7; 2, 1, 4; 1, 1, 5 for the patients with head‐and‐neck, abdomen, and chest cancer, respectively. The %GPs of global gamma indices for Mobius3D and MobiousFX were above 97%, while it ranged from 92% to 96% for ArcCHECK. The %GPs of individual volume‐based gamma indices were around 98% for Mobius3D and MobiousFX, except for γPTV for chest and abdominal cancer (88.9% to 92%); while it ranged from 86% to 99% for ArcCHECK. In conclusion, some differences in dosimetric metrics and gamma passing rates were observed with ArcCHECK measurement‐based QA in comparison with independent dosecheck and log files based QA. Care must be taken when considering replacing phantom measurement‐based IMRT/VMAT QA.
Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castration-resistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10–4; 7/7 vs. 10/59, P = 2.5 × 10–5; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxane-based chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.
Large Animal Models of Cell-Free Cardiac Regeneration

The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that can induce the heart to repair itself through cardiomyocyte proliferation, angiogenesis, and advantageous remodeling. Large animal models are an invaluable step toward translating basic research into clinical applications. In this review, we give an overview of the state-of-the-art in cell-free cardiac regeneration therapies that have been tested in large animal models, mainly pigs. Cell-free cardiac regeneration therapies involve stem cell secretome- and extracellular vesicles (including exosomes)-induced cardiac repair, RNA-based therapies, mainly regarding microRNAs, but also modified mRNA (modRNA) as well as other molecules including growth factors and extracellular matrix components. Various methods for the delivery of regenerative substances are used, including adenoviral vectors (AAVs), microencapsulation, and microparticles. Physical stimulation methods and direct cardiac reprogramming approaches are also discussed.
A bias‐corrected meta‐analysis model for combining, studies of different types and quality

Public health researchers may have to decide whether to perform a meta‐analysis including only high‐quality randomized clinical trials (RCTs) or whether to include a mixture of all the available evidence, namely RCTs of varying quality and observational studies (OS). The main hurdle when combining disparate evidence in a meta‐analysis is that we are not only combining results of interest but we are also combining multiple biases. Therefore, commonly applied meta‐analysis methods may lead to misleading conclusions.
CD44 + cells determine fenofibrate‐induced microevolution of drug‐resistance in prostate cancer cell populations

Combinations of metabolic blockers (including fenofibrate) with chemotherapeutic drugs interfere with the drug‐resistance of prostate cancer cells. However, their effect on cancer stem cells‐dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel‐resistant CD133high and/or CD44high cancer stem cell‐like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel‐resistant CD44negative “bulk” cells, thus accounting for the microevolution of drug‐resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug‐resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel‐ and docetaxel/fenofibrate‐treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long‐term propagation of drug‐resistant SCL‐derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug‐sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug‐resistant prostate tumors. However, docetaxel/fenofibrate‐induced selective expansion of hyper‐resistant CD44high SCL prostate cells and their “bulk” progenies prompts the microevolution of prostate tumor drug‐resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.
Factors associated with facial weakness following surgery for benign parotid disease: a retrospective multicenter study

ABSTRACT BACKGROUND: Facial nerve weakness is the most common and most concerning complication after parotidectomy. Risk factors for this complication following surgery for benign diseases remain controversial. OBJECTIVE: Review the frequency and prognosis of facial nerve weakness after parotidectomy and analyze potential risk factors. DESIGN: Retrospective review of medical records. SETTINGS: Two tertiary care centers. PATIENTS AND METHODS: We included all parotidectomies performed for benign diseases from January 2006 to December 2018. Details about the development and recovery of postoperative facial weakness were recorded. Patient, disease and surgery-related variables were analyzed using bivariate and multivariate analyses to identify risk factors. MAIN OUTCOME MEASURES: Frequency, recovery rates and risk factors for facial nerve weakness SAMPLE SIZE: 191 parotidectomies, 183 patients, 61 patients with facial weakness. RESULTS: The frequency of postoperative facial weakness was 31.9% (61/191 parotidectomies). Among patients with temporary weakness, 90% regained normal facial movement within 6 months. Steroid therapy was not associated with a faster recovery. Postoperative weakness was not associated with age, diabetes, smoking, disease location, use of an intraoperative facial nerve monitor or direction of facial nerve dissection. Risk factors for temporary weakness were total parotidectomy and surgical specimens larger than 60 cubic centimeters. Revision surgery was the only identified risk factor for permanent weakness. CONCLUSION: Larger parotid resections increase the risk of temporary facial nerve weakness while permanent weakness is mainly influenced by previous surgeries. LIMITATIONS: Retrospective nature, underpowered sample size, selection bias associated with tertiary care cases. CONFLICT OF INTEREST: None.
Physiological Stress Integrates Resistance to Rattlesnake Venom and the Onset of Risky Foraging in California Ground Squirrels

Using venom for predation often leads to the evolution of resistance in prey. Understanding individual variation in venom resistance is key to unlocking basic mechanisms by which antagonistic coevolution can sustain variation in traits under selection. For prey, the opposing challenges of predator avoidance and resource acquisition often lead to correlated levels of risk and reward, which in turn can favor suites of integrated morphological, physiological and behavioral traits. We investigate the relationship between risk-sensitive behaviors, physiological resistance to rattlesnake venom, and stress in a population of California ground squirrels. For the same individuals, we quantified foraging decisions in the presence of snake predators, fecal corticosterone metabolites (a measure of “stress”), and blood serum inhibition of venom enzymatic activity (a measure of venom resistance). Individual responses to snakes were repeatable for three measures of risk-sensitive behavior, indicating that some individuals were consistently risk-averse whereas others were risk tolerant. Venom resistance was lower in squirrels with higher glucocorticoid levels and poorer body condition. Whereas resistance failed to predict proximity to and interactions with snake predators, individuals with higher glucocorticoid levels and in lower body condition waited the longest to feed when near a snake. We compared alternative structural equation models to evaluate alternative hypotheses for the relationships among stress, venom resistance, and behavior. We found support for stress as a shared physiological correlate that independently lowers venom resistance and leads to squirrels that wait longer to feed in the presence of a snake, whereas we did not find evidence that resistance directly facilitates latency to forage. Our findings suggest that stress may help less-resistant squirrels avoid a deadly snakebite, but also reduces feeding opportunities. The combined lethal and non-lethal effects of stressors in predator–prey interactions simultaneously impact multiple key traits in this system, making environmental stress a potential contributor to geographic variation in trait expression of toxic predators and resistant prey.