Miracle-dz/UniFAR-FTUs huggingface dataset:
Low-dose sublingual fentanyl improves quality of life in patients with breakthrough cancer pain in palliative care.

Aim: This subanalysis of the CAVIDIOPAL study evaluated the impact of individualized management of breakthrough cancer pain (BTcP) with fentanyl on the quality of life (QoL) of advanced cancer patients in Spanish palliative care units. Patients & methods: This was a prospective, observational, multicenter study. The European Organization for Research and Treatment of Cancer's QLQ-C30 questionnaire was used at baseline (V0) and visit 28 (V28). Results: Ninety-five patients were mainly treated with 67-133 μg fentanyl, showing a notable reduction in intensity (visual analog scale: 8.0 [V0] to 4.6 [V28]), frequency and duration of BTcP episodes shortly after the first 1-2 weeks of treatment, with significantly improved QoL (global health status: 31.1 [V0] to 53.1 [V28]). Conclusion: Low-dose sublingual fentanyl effectively reduced BTcP in advanced cancer patients in palliative care units, significantly improving QoL. Clinical trial registration: NCT02840500 (ClinicalTrials.gov).
The notion of Surrogacy in Health Technology Assessment: an insight in the processes of Germany, UK and France

The notion of Health Technology Assessment (HTA) has evolved significantly since its inception and currently it is acclaimed as the holy grail of decision-making in the pharmaceutical sector. The elaboration of an HTA report constitutes a resource and time-demanding process. In this saga, overall survival (OS) has been acknowledged as the gold standard in elucidating the value of an oncology treatment modality, broadcasting what matters the most to patients and the community. OS along with health-related quality of life (HRQOL), falls under the “patient-centered clinical endpoints”. Patient-centered clinical endpoints describe the endpoints that measure a direct patient clinical benefit, such as individuals’ survival or feeling of wellbeing. In principle, clinical trials should focus on OS. However, in certain cases, it is hard or even unattainable for companies to submit mature OS data since the evolution in the pharmaceutical sector has led to significant survival gains. In this sense, the timeframe of a single trial is usually insufficient to capture the full spectrum of OS. Moreover, the design of trials, as in the case of cross-over studies, further hampers the use and the clarity of OS as an endpoint. In this backdrop, much effort may be devoted to validate surrogate endpoints; however, surrogate endpoints are used specifically because they are more easily accessible. Discovery and validation of surrogate endpoints, which can be gathered at an early stage of the disease and most significantly, can demonstrate strong predictive causality with OS. In oncology, surrogate endpoints are tumor-centered clinical endpoints that infer clinical benefit to the patient and are employed as a proxy for a patient-centered clinical endpoint. These endpoints refer to biological markers, either laboratory or histology ones, such as tumor response, circulating tumor cells, disease-free survival (DFS) and progression-free survival (PFS), which can define therapeutic response to an intervention. The rationale of surrogate endpoints is nested in the prediction of survival well in advance, thus perpetuating to fewer patients and shorter and cheaper trials. In some cases, as in the cases of crossover to subsequent treatments, the use of surrogate endpoints is justified. A validation must precede, which constitutes an intricate but obligatory process. Many surrogate endpoints, which meet the criteria of being assessable earlier in a patient’s life, have been assessed. Nevertheless, a simple correlation does not suffice (Table 1). The surrogate endpoints, according to Prentice, must meet four operational criteria:
Nitric oxide stimulates type IV MSHA pilus retraction in Vibrio cholerae via activation of the phosphodiesterase CdpA

Significance All organisms sense and respond to their environments. One way bacteria interact with their surroundings is by dynamically extending and retracting filamentous appendages from their surface called pili. While pili are critical for many functions, such as attachment, motility, and DNA uptake, the factors that regulate their dynamic activity are poorly understood. Here, we describe how an environmental signal induces a signaling pathway to promote the retraction of mannose-sensitive hemagglutinin pili in Vibrio cholerae. The retraction of these pili promotes the detachment of V. cholerae from a surface and may provide a means by which V. cholerae can respond to changes in its environment. Bacteria use surface appendages called type IV pili to perform diverse activities including DNA uptake, twitching motility, and attachment to surfaces. The dynamic extension and retraction of pili are often required for these activities, but the stimuli that regulate these dynamics remain poorly characterized. To address this question, we study the bacterial pathogen Vibrio cholerae, which uses mannose-sensitive hemagglutinin (MSHA) pili to attach to surfaces in aquatic environments as the first step in biofilm formation. Here, we use a combination of genetic and cell biological approaches to describe a regulatory pathway that allows V. cholerae to rapidly abort biofilm formation. Specifically, we show that V. cholerae cells retract MSHA pili and detach from a surface in a diffusion-limited, enclosed environment. This response is dependent on the phosphodiesterase CdpA, which decreases intracellular levels of cyclic-di-GMP to induce MSHA pilus retraction. CdpA contains a putative nitric oxide (NO)–sensing NosP domain, and we demonstrate that NO is necessary and sufficient to stimulate CdpA-dependent detachment. Thus, we hypothesize that the endogenous production of NO (or an NO-like molecule) in V. cholerae stimulates the retraction of MSHA pili. These results extend our understanding of how environmental cues can be integrated into the complex regulatory pathways that control pilus dynamic activity and attachment in bacterial species.
Identification and mapping of bs8, a novel locus conferring resistance to bacterial spot caused by Xanthomonas gardneri.

Although cultivars possessing recessive resistance alleles provide effective control bacterial of spot of pepper (Capsicum annuum), the currently deployed resistance gene, bs5, is ineffective against Xanthomonas gardneri (Xg), one of the pathogenic species. Resistance against Xg was identified in C. annuum accession PI 163192, and this study sought to characterize this novel resistance and to map the resistance gene(s) to the pepper genome. We crossed PI 163192 with the susceptible cultivar, Early Calwonder (ECW), to develop resistant near-isogenic lines (NILs) of ECW, designated ECW80R. The novel resistance in ECW80R was determined to be quantitative, recessively inherited, and non-HR causing, and inhibits lesion expansion and chlorosis. Presence of the resistance in NILs decreased the in planta bacterial population by 9-fold compared to ECW. Bulked segregant analysis (BSA) of resistant and susceptible individuals from an F2 population using whole genome single nucleotide polymorphisms identified a major resistance locus within an approximately 6 Mb interval on the sub-telomeric region of chromosome 11. We developed markers spanning this region and used these to genotype backcross F2 populations, which further delimited the resistance locus within a 2.3 Mb interval. The novel resistance locus has been designated bs8. ECW80R and the linked markers developed in this study should prove useful for breeders seeking to advance this resistance into commercially-relevant germplasm and for pyramiding bs8 with other resistance alleles such as bs5 and bs6. bs8 will help prolong the durability of bacterial spot resistance in pepper and improve resistance to multiple species of Xanthomonas.
Comparison of National Growth Standards for Turkish Infants and Children with World Health Organization Growth Standards

Objective: Using World Health Organization (WHO) standards in pediatric practice is still controversial in many countries. It is suggested that national growth charts best reflect the genetic and ethnic characteristics of a population. The aim of this study was to compare length/height, body weight, and body mass index (BMI) in healthy Turkish children of ages 0 to 18 with those proposed by WHO as the international growth standards. Methods: The data of Turkish children were collected from infant/child population aged 0-5 years (2391 boys, 2102 girls) and children of ages between 6-18 years (1100 boys, 1020 girls). For comparison, the 50th, 3rd, and 97th percentile curves for length/height, weight, and BMI in Turkish children were plotted together with respective WHO data. Results: Heights were essentially similar in the Turkish and WHO data at ages between 3-10 years. Turkish children were markedly taller compared to the WHO standards after the age of 10 years. Evaluation of the 3rd percentile data revealed that Turkish boys were shorter than the WHO subjects in the first 2 years of life. From 6 months of age, Turkish children showed higher weight for age values in the 3rd, 50th, and 97th percentiles. In all age groups between 6 months and 3 years, and in between 6-18 years of age, Z-score values, as well as the 50th, 15th, 85th, and 95th percentile values were higher in Turkish children. The differences were particularly noteworthy at ages 1-2 years and in the pubertal years. Conclusion: WHO growth standards do not reflect the growth of Turkish children and may substantially alter the prevalence of short stature and underweight in Turkish children in the 0-5 years age group. When assessing the nutritional and growth status of children, national growth standards may be more appropriate.
Non-invasive oocyte quality assessment

Abstract Oocyte quality is perhaps the most important limiting factor in female fertility; however, the current methods of determining oocyte competence are only marginally capable of predicting a successful pregnancy. We aim to review the predictive value of non-invasive techniques for the assessment of human oocytes and their related cells and biofluids that pertain to their developmental competence. Investigation of the proteome, transcriptome, and hormonal makeup of follicular fluid, as well as cumulus-oocyte complexes are currently underway; however, prospective randomized non-selection-controlled trials of the future are needed before determining their prognostic value. The biological significance of polar body morphology and genetics are still unknown and the subject of debate. The predictive utility of zygotic viscoelasticity for embryo development has been demonstrated, but similar studies performed on oocytes have yet to be conducted. Metabolic profiling of culture media using human oocytes are also limited and may require integration of automated, high-throughput targeted metabolomic assessments in real time with microfluidic platforms. Light exposure to oocytes can be detrimental to subsequent development and utilization of time-lapse imaging and morphometrics of oocytes is wanting. Polarized light, Raman microspectroscopy, and coherent anti-Stokes Raman scattering are a few novel imaging tools that may play a more important role in future oocyte assessment. Ultimately, the integration of chemistry, genomics, microfluidics, microscopy, physics, and other biomedical engineering technologies into the basic studies of oocyte biology, and in testing and perfecting practical solutions of oocyte evaluation, are the future for non-invasive assessment of oocytes. Summary Sentence Direct and/or indirect non-invasive assessments of oocyte quality are reviewed and discussed in relation to clinical needs in assisted reproductive technologies and as informative underpinnings of basic reproductive biology spanning follicle to embryo development.
Outcome of children with relapsed high-risk neuroblastoma in Japan and analysis of the role of allogeneic hematopoietic stem cell transplantation.

BACKGROUND In Japan, allogeneic hematopoietic stem cell transplantation is widely performed for recurrent neuroblastomas. This retrospective study aimed to investigate the prognosis of recurrent neuroblastoma in Japan and explore the effectiveness of allogeneic hematopoietic stem cell transplantation. METHODS Clinical characteristics and data on the treatment of patients with high-risk neuroblastoma who experienced first progression between 2003 and 2010 after attaining complete remission or partial remission were collected from hospitals participating in the Japanese Neuroblastoma Research Group. RESULTS Data from 61 patients who fulfilled these criteria were collected. The median interval from disease onset to first progression was 19 months (range, 7-65 months), whereas the median observation time of the surviving patients was 18 months (range, 1-69 months). All patients were treated with chemotherapy, where 22 and 3 patients received allogeneic and autologous hematopoietic stem cell transplantation, respectively. Seven patients were alive in second complete remission, and 39 died, including two in complete remission. The 3-year progression-free survival and overall survival rates were 15.3% (SE: 6.1%) and 16.9% (SE: 6.5%), respectively. For patients with allogeneic hematopoietic stem cell transplantation, the 3-year progression-free survival and overall survival were 28.3% (standard error, 12.0%) and 24.3% (standard error, 11.5%), respectively, and for patients without allogeneic hematopoietic stem cell transplantation, the 3-year progression-free survival and overall survival were 6.0% (standard error 5.5%) and 12.0% (standard error 7.6%), respectively. The duration of initial remission (≥ 18 months) and implementation of allogeneic hematopoietic stem cell transplantation were independently predictive of progression-free survival (P = 0.002 and P = 0.017), whereas for overall survival, only allogeneic hematopoietic stem cell transplantation was predictive (P = 0.012). CONCLUSION Although allogeneic hematopoietic stem cell transplantation contributed to some improvement in prognosis, it was insufficient.
Value of multi-slice spiral computerized tomography for diagnosis of synchronous colorectal carcinoma: a retrospective study

Objective To compare the accuracy of multi-slice spiral computerized tomography (MSCT) with colonoscopy for diagnosing synchronous colorectal carcinoma (SCC). Methods We retrospectively analyzed all consecutive patients admitted to our institution with colorectal carcinoma between 19 September 2014 and 31 January 2020. Data on SCC patients who had undergone MSCT and colonoscopy were analyzed. Information on tumor location, tumor size, missed diagnosis by MSCT or colonoscopy, T stage, pathological type, and reasons for missed diagnosis was recorded and used to assess the diagnostic accuracies of MSCT and colonoscopy. Results Twenty-three cases met the inclusion criteria. MSCT plus colonoscopy had a significantly higher diagnostic accuracy (93.5%) than colonoscopy alone. There were significant differences in missed diagnosis rates of proximal cancer (34.8%) and distal cancer (4.3%) by colonoscopy. For MSCT, the missed diagnosis rate for tumors with a median long diameter of 1.25 cm (interquartile range 0.80, 1.50) was significantly lower than that for larger tumors (long diameter 4.00 cm; 3.00, 6.00). Conclusions MSCT is a valuable diagnostic tool for SCC that can effectively minimize the missed diagnosis rate of primary tumors when combined with colonoscopy.
The RB1CC1 Claw-binding motif: a new piece in the puzzle of autophagy regulation

ABSTRACT RB1CC1/FIP200 is a subunit of the ULK1 complex in more complex eukaryotes. This large polypeptide was proposed to be a functional homolog of the Atg17 and Atg11 scaffolding proteins in yeast. Previous studies showed that RB1CC1 can bind to various proteins of the macroautophagy/autophagy machinery, where the RB1CC1 Claw domain directly interacts with a short linear segment of its interactors. A mechanistic insight into how the small globular RB1CC1 Claw domain can interact with such an array of structurally variable proteins has been elusive. The recent study by Zhou et al., discussed here, yields structural data that not only provide a unifying mechanistic explanation of these interactions, but also reveals previously unknown RB1CC1 interactors and opens a new field for exploration of autophagy regulation. Abbreviations: FIR: FIP200-interacting region; LIR: LC3-interacting region; pS/p-S: phosphorylated serine
Intrathecal Synthesis Index of Specific Anti-Treponema IgG: a New Tool for the Diagnosis of Neurosyphilis

In the context of a lack of a gold standard for the diagnosis of neurosyphilis due to either nonspecific or nonsensitive tests, we present in this article a new promising tool highly specific for NS diagnosis. This new test involves measuring an intrathecal synthesis index of specific anti-Treponema IgG by ELISA. ABSTRACT Neurosyphilis (NS) diagnosis is challenging because clinical signs are diverse and unspecific, and a sensitive and specific laboratory test is lacking. We tested the performance of an antibody index (AI) for intrathecal synthesis of specific anti-Treponema IgG by enzyme-linked immunosorbent assay (ELISA) for NS diagnosis. We conducted a retroprospective monocentric study including adults with neurological symptoms who had serum and cerebral spinal fluid (CSF) samples collected between 2006 and 2021. Two NS definitions were used. NS1 included patients with neurological symptoms, positive Treponema pallidum particle agglutination (TPPA) serology, and CSF-TPPA of ≥320, as well as CSF-leukocytes of >5 cells/mm3 and/or CSF-protein of >0.45 g/L and/or a reactive CSF-VDRL/RPR test. NS2 included patients with acute ocular and/or otologic symptoms, positive TPPA serology, and a response to NS treatment. Controls were patients with central nervous system disorders other than neurosyphilis. Anti-Treponema pallidum IgG were measured simultaneously in serum and CSF, and AI was calculated according to Reiber diagram. We assessed the AI test area under the curve (AUC), sensitivity/specificity, and estimated positive and negative predictive values. In total, 16 NS1 patients, 11 NS2 patients, and 71 controls were included. With an AI of ≥1.7 as a positive test for NS diagnostic, specificity was 98.6% (95% confidence interval [CI 95%] of 92.4 to 100.0) and sensitivity was 81.3% (CI 95% of 54.4 to 96.0) for NS1 and 98.6% (CI 95% 92.4 to 100.0) and 27.3% (CI 95% 6.0 to 61.0), respectively, for NS2. Positive and negative predictive values were >95% for NS1 and >85% for NS2, for prevalence above and below 20%. Measuring an AI for intrathecal synthesis of specific anti-Treponema pallidum IgG is a new promising tool highly specific for NS diagnosis. IMPORTANCE In the context of a lack of a gold standard for the diagnosis of neurosyphilis due to either nonspecific or nonsensitive tests, we present in this article a new promising tool highly specific for NS diagnosis. This new test involves measuring an intrathecal synthesis index of specific anti-Treponema IgG by ELISA.
Comparative Bioavailability Study of Solid Self-Nanoemulsifying Drug Delivery System of Fenofibric Acid in Healthy Male Subjects

Objective: This study aimed to evaluate the effect of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formation on the bioavailability of fenofibric acid. Subject and Methods: Three formulations of fenofibric acid, namely, S-SNEDDS containing medium-chain triglyceride (FS1), S-SNEDDS containing long-chain triglyceride (FS2), and FSt as tablet of innovator product, were used in this study. Bioavailability study was conducted in 12 Indonesian healthy male subjects after a single-dose administration of each formulation with three-way crossover design. Blood samples were collected from 0 to 72 h after drug administration and then analyzed using the high-performance liquid chromatography method. Data were statistically analyzed using the ANOVA and the Wilcoxon signed-rank test using a p value of 0.05. Dissolution test was carried out with USP dissolution apparatus using three medium (pH 1.2, 4.5 and 6.8). Results: The rates of absorption of fenofibric acid from S-SNEDDS FS1 and FS2 were significantly increased about 1.78 and 2.40 times, respectively, relative to FSt. Tmax values of FS1 and FS2 were shorter than FSt, namely, 0.96 ± 0.438 h (FS1), 0.71 ± 0.445 h (FS2), and 1.71 ± 0.840 h (FSt), respectively. Meanwhile, the Cmax and AUC values of FS1, FS2, and FSt were found to be not significantly different with a p value of >0.05. S-SNEDDS formation increased the dissolution rate in acid medium. Conclusions: S-SNEDDS increased the dissolution rate in acid medium and absorption rate of fenofibric acid but did not increase the extent of fenofibric acid absorption.
Pramlintide for post‐bariatric hypoglycaemia

The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post‐bariatric hypoglycaemia (PBH).
miR-139-3p/Kinesin family member 18B axis suppresses malignant progression of gastric cancer

ABSTRACT miR-139-3p exerts tumor-suppressing functions in various cancers. We analyzed and identified that miR-139-3p expression was notably low in gastric cancer (GC) via edgeR differential analysis based on The Cancer Genome Atlas database and quantitative real-time polymerase chain reaction (qRT-PCR) assay. The binding relationship between Kinesin Family Member 18B (KIF18B) and miR-139-3p was predicted by bioinformatics databases, and verified through dual-luciferase assay. Western blot and qRT-PCR results also indicated that miR-139-3p restrained KIF18 expression at mRNA and protein levels. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, transwell, flow cytometry assays were introduced to evaluate cell proliferation, migration, invasion, and cell cycle, respectively, where the results indicated that upregulating miR-139-3p inhibited proliferative, migratory, and invasive abilities of GC cells, while caused cell-cycle arrest. Moreover, the results of rescue experiments illustrated that miR-139-3p hampered the progression of GC cells by targeting and suppressing KIF18B. To sum up, we concluded that miR-139-3p suppressed GC progression by targeting KIF18B. GRAPHICAL ABSTRACT