Miracle-dz/UniFAR-FTUs huggingface dataset:
Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)

PURPOSE The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873). RESULTS Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option. Addition of panitumumab to maintenance therapy with 5-FU/FA improves outcome in RAS WT metastatic colorectal cancer.
The increased presence of repetitive motifs in the KDDR-plus recombinant protein, a kinesin-derived antigen from Leishmania infantum, improves the diagnostic performance of serological tests for human and canine visceral leishmaniasis

Visceral leishmaniasis (VL) is caused by protozoa belonging to the Leishmania donovani complex and is considered the most serious and fatal form among the different types of leishmaniasis, if not early diagnosed and treated. Among the measures of disease control stand out the management of infected dogs and the early diagnosis and appropriate treatment of human cases. Several antigens have been characterized for use in the VL diagnosis, among them are the recombinant kinesin-derived antigens from L. infantum, as rK39 and rKDDR. The main difference between these antigens is the size of the non-repetitive kinesin region and the number of repetitions of the 39 amino acid degenerate motif (6.5 and 8.5 repeats in rK39 and rKDDR, respectively). This repetitive region has a high antigenicity score. To evaluate the effect of increasing the number of repeats on diagnostic performance, we designed the rKDDR-plus antigen, containing 15.3 repeats of the 39 amino acid degenerate motif, besides the absence of the non-repetitive portion from L. infantum kinesin. Its performance was evaluated by enzyme-linked immunosorbent assay (ELISA) and rapid immunochromatographic test (ICT), and compared with the kinesin-derived antigens (rKDDR and rK39). In ELISA with human sera, all recombinant antigens had a sensitivity of 98%, whereas the specificity for rKDDR-plus, rKDDR and rK39 was 100%, 96% and 71%, respectively. When evaluated canine sera, the ELISA sensitivity was 97% for all antigens, and the specificity for rKDDR-plus, rKDDR and rK39 was 98%, 91% and 83%, respectively. Evaluation of the ICT/rKDDR-plus, using human sera, showed greater diagnostic sensitivity (90%) and specificity (100%), when compared to the IT LEISH (79% and 98%, respectively), which is based on the rK39 antigen. These results suggest that the increased presence of repetitive motifs in the rKDDR-plus protein improves the diagnostic performance of serological tests by increasing the specificity and accuracy of the diagnosis.
Approaches to oocyte meiotic arrest in vitro and impact on oocyte developmental competence

Abstract Oocytes are maintained in a state of meiotic arrest following the first meiotic division until ovulation is triggered. Within the antral follicle, meiotic arrest is actively suppressed in a process facilitated by the cyclic nucleotides cGMP and cAMP. If removed from this inhibitory follicular environment and cultured in vitro, mammalian oocytes undergo spontaneous meiotic resumption in the absence of the usual stimulatory follicular stimuli, leading to asynchronicity with oocyte cytoplasmic maturation and lower developmental competence. For more than 50 years, pharmacological agents have been used to attenuate oocyte germinal vesicle (GV) breakdown in vitro. Agents that increase intra-oocyte cAMP or prevent its degradation have been predominantly used; however, agents such as kinase and protein synthesis inhibitors have also been trialed. Twenty years of research demonstrates that maintaining GV arrest for a period before in vitro maturation (IVM) improves oocyte developmental competence, and is likely attributed to maintenance of bidirectional communication with cumulus cells leading to improved oocyte metabolic function. However, outcomes are influenced by various factors including the mode of action of the modulators, dose, treatment duration, species, and the degree of hormonal priming of the oocyte donor. Cyclic GMP and/or cAMP modulation in a prematuration step (called pre-IVM) prior to IVM has shown the greatest consistency in improving oocyte developmental competence, whereas kinase and protein synthesis inhibitors have proven less effective at improving IVM outcomes. Such pre-IVM approaches have shown potential to alter current use of artificial reproductive technologies in medical and veterinary practice.
Evaluating oliceridine as a treatment option for moderate to severe acute post-operative pain in adults

ABSTRACT Introduction Despite the advances in regional anesthesia and non-opioid systemic analgesia, opioids remain the primary rescue analgesic for moderate to severe pain. However, the risks and side effects of opioid medications are well documented. Oliceridine is a novel opioid receptor agonist which is thought to have less risk of adverse events, such as postoperative nausea and vomiting (PONV) and respiratory depression. Areas Covered In this review, the authors discuss the limitations of the current opioid and non-opioid analgesic options. They also review the pharmacokinetics of oliceridine, its analgesic efficacy, and risk of adverse events; and its added clinical value in managing moderate to severe pain. Expert opinion Despite the advances in regional anesthesia and multimodal systemic analgesia, opioid free analgesia is only feasible in selected procedures and patients. Oliceridine is effective in the management of moderate to severe pain and appears to be associated with lower risk of nausea and vomiting. The risk of sedation and respiratory depression associated with oliceridine will require further study. The availability of an opioid agonist with a better side effect profile could potentially change the current paradigm of opioid avoidance in postoperative pain management.
Altered expression of junctional proteins as a potential biomarker in oral precancerous and cancerous patients

ABSTRACT Due to a lower survival rate in patients with advanced clinical stages of oral cancer, discovering a biomarker that could diagnose and predict disease progression is vital. Cell–cell junctional proteins play a crucial role in the maintenance of tissue architecture but are often deregulated in different cancer. The present study investigates the expression of cell–cell junctional proteins viz: e-cadherin (E-cad) and zonula occludens-1 (ZO-1) in oral precancerous (OED) and cancerous (OSCC) patients to monitor if they can serve as practicable molecular markers. The ultrastructural junctional complex was studied by transmission electron microscopy, and the expression of proteins was performed by immunohistochemistry. The relationship between the expression of protein and clinicopathological features of the patients was checked by Pearson’s correlation test. Furthermore, the survival curve of the follow-up data was estimated by the Kaplan–Meier method. We observed a disrupted junctional complex and a significantly decreased immunoexpression of E-cad and ZO-1 in OED and OSCC when compared to the adjacent non-cancerous tissues. The expression of ZO-1 was associated with TNM stages, whereas E-cad was associated with histological grades as well as TNM stages. A positive correlation was observed between the expression of ZO-1 and E-cad proteins in OED and OSCC. Further, follow-up studies revealed that high ZO-1 and E-cad expressing patients survived longer than their low expressed counterparts. The present study shows disruption of junctional complex and alteration of junctional proteins expression that could draw the attention of health professionals to explore junctional proteins as a possible therapeutic target in oral cancer.
EEG-based emotion classification using LSTM under new paradigm

Deep learning has gained much popularity in solving challenging machine learning problems related to image, speech classification, etc. Research has been conducted to apply deep learning models in emotion classification based on physiological signals such as EEG. Most of the research works have based their model on the spatial aspects of the EEG. However, the emotion features in EEG are spread across the time domain during an emotional episode. Therefore, in this work, the emotion classification problem is modelled as a sequence classification problem. The power band frequency based features of every time segment of EEG sequences generated from 32-channel EEG data are used to train three different models of Long Short-Term Memory (LSTM1, LSTM2, and LSTM3). Four class (HVHA, HVLA, LVHA, and LVLA) classification experiments were performed based on the valence and arousal emotion models. The LSTM3 model with 128 memory cells achieved the highest classification accuracy of 90%, whereas LSTM1 (32 cells) and LSTM2 (64 cells) yielded classification accuracies of 85% and 89% respectively. Further, the impact of segment size on classification accuracy was also investigated in this work. Results obtained indicate that a smaller segment size leads to higher classification accuracy using LSTM models.
The role of Bruton's tyrosine kinase in the immune system and disease

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B‐cell biology and function, highlighted by its position as a critical component of the B‐cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID‐19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.
Oriented in situ immobilization of a functional tyrosinase on microcrystalline cellulose effectively incorporates DOPA residues in bioengineered mussel adhesive protein

Catechol‐containing polymers such as mussel adhesive proteins (MAPs) are attractive as biocompatible adhesive biomaterials, and the catecholic amino acid 3,4‐dihydroxyphenyl‐L‐alanine (DOPA) is considered a key molecule in underwater mussel adhesion. Tyrosinases can specifically convert tyrosine to DOPA without any cofactors. However, their catalytic properties still need to be adjusted to minimize unwanted DOPA oxidation via their diphenolase activity and catechol instability at neutral and basic pH values in the reaction products.
Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension

While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side‐specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern‐specific endocardial signaling controls the elongation of leaflets.
Brain regionalization by Polycomb‐group proteins and chromatin accessibility

During brain development, neural precursor cells (NPCs) in different brain regions produce different types of neurons, and each of these regions plays a different role in the adult brain. Therefore, precise regionalization is essential in the early stages of brain development, and irregular regionalization has been proposed as the cause of neurodevelopmental disorders. The mechanisms underlying brain regionalization have been well studied in terms of morphogen‐induced expression of critical transcription factors for regionalization. NPC potential in different brain regions is defined by chromatin structures that regulate the plasticity of gene expression. Herein, we present recent findings on the importance of chromatin structure in brain regionalization, particularly with respect to its regulation by Polycomb‐group proteins and chromatin accessibility.
Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity

Methamphetamine (METH) is a potent psychostimulant that increases extracellular monoamines, such as dopamine and norepinephrine, and affects multiple tissue and cell types in the central nervous system (CNS) and peripheral immune cells. The reinforcing properties of METH underlie its significant abuse potential and dysregulation of peripheral immunity and central nervous system functions. Together, the constellation of METH’s effects on cellular targets and regulatory processes has led to immune suppression and neurodegeneration in METH addicts and animal models of METH exposure. Here we extensively review many of the cell types and mechanisms of METH-induced dysregulation of the central nervous and peripheral immune systems. SIGNIFICANCE STATEMENT Emerging research has begun to show that methamphetamine regulates dopaminergic neuronal activity. In addition, METH affects non-neuronal brain cells, such as microglia and astrocytes, and immunological cells of the periphery. Concurrent disruption of bidirectional communication between dopaminergic neurons and glia in the CNS and peripheral immune cell dysregulation gives rise to a constellation of dysfunctional neuronal, cell, and tissue types. Therefore, understanding the pathophysiology of METH requires consideration of the multiple targets at the interface between basic and clinical neuroscience.
Current emerging MRI tools for radionecrosis and pseudoprogression diagnosis

Purpose of review This review aims to cover current MRI techniques for assessing treatment response in brain tumors, with a focus on radio-induced lesions. Recent findings Pseudoprogression and radionecrosis are common radiological entities after brain tumor irradiation and are difficult to distinguish from real progression, with major consequences on daily patient care. To date, shortcomings of conventional MRI have been largely recognized but morphological sequences are still used in official response assessment criteria. Several complementary advanced techniques have been proposed but none of them have been validated, hampering their clinical use. Among advanced MRI, brain perfusion measures increase diagnostic accuracy, especially when added with spectroscopy and susceptibility-weighted imaging. However, lack of reproducibility, because of several hard-to-control variables, is still a major limitation for their standardization in routine protocols. Amide Proton Transfer is an emerging molecular imaging technique that promises to offer new metrics by indirectly quantifying intracellular mobile proteins and peptide concentration. Preliminary studies suggest that this noncontrast sequence may add key biomarkers in tumor evaluation, especially in posttherapeutic settings. Summary Benefits and pitfalls of conventional and advanced imaging on posttreatment assessment are discussed and the potential added value of APT in this clinicoradiological evolving scenario is introduced.
Mechanism of catalytic ozonation in expanded graphite aqueous suspension for the degradation of organic acids

ABSTRACT In this study, expanded graphite (EG) was prepared by the oxidation and intercalation of the natural flake graphite using perchloric acid and potassium permanganate at different expansion temperatures (300, 400, 500, and 600°C), and were characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). EG prepared at 500°C was found to be highly effective for the mineralization of oxalic acid aqueous solution during ozonation at pH 3, which was ascribed to the formation of hydroxyl radicals from the surface reaction of surface hydroxyl groups on EG with ozone. The performance of expanded graphite in this catalytic system was basically unchanged after three repeated use. The presence of Cl−, , and could inhibit the degradation of oxalic acid in catalytic ozonation with EG. Degradations of oxamic acid and pyruvic acid in catalytic ozonation with EG were pH-dependent, which were lower than that of oxalic acid. The degradations of oxalic acid and oxamic acid were identified as mineralization process by the determination of TOC, while pyruvic acid may transform into organic products such as acetic acid by O3/EG. Manganese ion (Mn2+) could promote the degradation of oxalic acid by O3/EG at pH 3 because permanganate was produced by O3/EG in oxalic acid solution and then reacted with oxalic acid readily at acidic pH. Catalytic ozonation by EG exhibited great application potential for the destruction of refractory organic compounds. GRAPHICAL ABSTRACT
Laparoscopic Versus Open Simultaneous Resection of Primary Colorectal Cancer and Associated Liver Metastases: A Comparative Retrospective Study

Purpose: The aim was to compare the short-term and long-term outcomes of patients with metastatic colorectal cancer (CRC) undergoing laparoscopic versus open colorectal resection with simultaneous resection for liver metastases. Currently there is a lack of studies that have investigated the oncosurgical aspects and the short and long-term outcomes from these procedures. Materials and Methods: A retrospective study of patients who underwent simultaneous resections for CRC and synchronous liver metastases between 2008 and 2019 in 2 university affiliated medical centers. Results: Sixty-three patients were identified of whom 21 had successful laparoscopic simultaneous resections. In 43% of patients, the primary tumor was located in the right colon. The 3-year overall survival and disease-free survival rates were 87% and 48%, respectively. When compared with a separate control group of 42 patients who underwent conventional open resections, the laparoscopic approach was associated with an increased operative time (286 vs. 225 min, P=0.05), but a shorter hospital stay (6 vs. 8 d, P=0.008). Conclusions: Simultaneous laparoscopic colorectal and parenchymal sparing liver resection for metastatic CRC is safe, feasible, and it is a preferable approach because of better short-term outcome compared with open surgery while not compromising survival and disease recurrence.
MUC5AC serves as the nexus for β-catenin/c-Myc interplay to promote glutamine dependency during pancreatic cancer chemoresistance.

BACKGROUND AND AIMS A major clinical challenge for pancreatic cancer (PC) patients is metabolic adaptation. Neoplastic cells harboring molecular perturbations suffice for their increased anabolic demand and nucleotide biosynthesis to acquire chemoresistance. The mucin 5AC expressed de novo in malignant pancreas promotes cancer cell stemness and is significantly associated with poor patient survival. Identification of MUC5AC-associated drivers of chemoresistance through metabolic alterations may facilitate sculpting a new combinatorial regimen. METHODS The contribution of MUC5AC on glutaminolysis and gemcitabine resistance were examined by TCGA data analysis, RNA sequencing, and immunohistochemistry analysis on pancreatic tissues of KrasG12D; Pdx1-Cre (KC) and KrasG12D; Pdx1-Cre; Muc5ac-/- (KCM) mice. These were followed by metabolite flux assays, biochemical and xenograft studies on MUC5AC-depleted human and murine PC cells. Murine and human pancreatic 3D-tumoroids were used to evaluate gemcitabine's efficacy in combination with β-catenin and glutaminolysis inhibitors. RESULTS Transcriptional analysis demonstrated that high MUC5AC-expressing human and autochthonous murine PC tumors exhibit higher resistance to gemcitabine due to enhanced glutamine utilization and nucleotide biosynthesis. Gemcitabine treatment led to MUC5AC overexpression, resulting in disruption of E-Cadherin/β-catenin junctions and the nuclear translocation of β-catenin, which increased c-Myc expression with a concomitant rise in glutamine uptake and glutamate release. MUC5AC-depletion and glutamine deprivation sensitized human PC cells to gemcitabine, which was obviated by glutamine replenishment in MUC5AC-expressing cells. Co-administration of β-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated resistance in murine and human tumoroids. CONCLUSIONS MUC5AC/β-catenin/c-Myc axis increases the uptake and utilization of glutamine in PC cells and co-targeting this axis along with gemcitabine may improve the therapeutic efficacy in PC.