Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.
Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF‐7 human breast cancer cell line

Despite advances in treatment, breast cancer remains the widest spread disease among females with a high mortality rate. We investigated the potential effects of gallic acid (GA) as supportive therapy in the management of breast cancer. Anti‐cancer activity with GA alone or in combination with paclitaxel and/or carboplatin was assessed by MTT assay and flow cytometry using annexin V/propidium iodide. The mechanism underlying the antiproliferative effects was investigated by measuring the expression of the pro‐apoptotic marker (Bax), CASP‐3, anti‐apoptotic (Bcl‐2), and, tumor suppressor (p53) by real‐time polymerase chain reaction (RT‐PCR) and western blot analysis. Cell cycle analysis was performed for the MCF‐7 breast cancer cell line. GA, paclitaxel, and carboplatin alone or in combination arrested cell cycle progression at the G2/M phase and induced Pre‐G1 apoptosis. RT‐PCR showed that the triplet combination significantly raised P53, Bax, and CASP‐3 mRNA expression (20.1 ± 1.41, 16.6 ± 0.43, and 20.04 ± 1.61, respectively) in MCF‐7 cells when compared to single or combined treatment (p < .0001) while anti‐apoptotic Bcl‐2 mRNA levels were decreased in all treated groups compared to untreated cells. Western blot data of tested apoptotic factors were consistent with RT‐PCR results. For the first time, we show that a minimum non‐toxic concentration of GA increased the efficacy of paclitaxel‐ and carboplatin‐induced MCF‐7 apoptotic cell death.
Role of POT1 in Human Cancer

Simple Summary The segmentation of eukaryotic genomes into discrete linear chromosomes requires processes to solve several major biological problems, including prevention of the chromosome ends being recognized as DNA breaks and compensation for the shortening that occurs when linear DNA is replicated. A specialized set of six proteins, collectively referred to as shelterin, is involved in both of these processes, and mutations in several of these are now known to be involved in cancer. Here, we focus on Protection of Telomeres 1 (POT1), the shelterin protein that appears to be most commonly involved in cancer, and consider the clinical significance of findings about its biological functions and the prevalence of inherited and acquired mutations in the POT1 gene. Abstract Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib

Key Points Question Does adding ipilimumab to nivolumab improve clinical outcomes for patients with advanced hepatocellular carcinoma previously treated with sorafenib? Findings In the CheckMate 040 randomized clinical trial of nivolumab plus ipilimumab in patients with advanced hepatocellular cancer previously treated with sorafenib, patients were randomized 1:1:1 to 3 different treatment arms to evaluate different dosing regimens. Investigator-assessed objective response rate was greater than 30% across treatment arms, and the combination of nivolumab plus ipilimumab led to high overall survival rates and had a manageable safety profile. Meaning The manageable safety profile and promising response rates observed in this study support further investigation of nivolumab plus ipilimumab as a treatment option for this patient population.
A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization’s (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.
Time to the Peak, Shape of the Curve and Combination of These Glucose Response Characteristics During Oral Glucose Tolerance Test as Indicators of Early Beta-cell Dysfunction in Obese Adolescents

Objective: Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT). Methods: Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/≥60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI). Results: Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001]. Conclusion: Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.
Patient-Centered Care in Psoriatic Arthritis—A Perspective on Inflammation, Disease Activity, and Psychosocial Factors

Psoriatic arthritis (PsA) is a seronegative spondyloarthropathy characterized by skin lesions, dactylitis, and enthesitis. Patients with PsA suffer from a variety of psychosocial difficulties and nonspecific symptoms early on in the disease course and continue to experience progressive disease due to delays in diagnosis and treatment. Symptoms initially viewed as somatization could lead to undertreatment and promote psychological distress, poor coping, and negative patient–provider relationships. Pain and fatigue are important complaints that affect the patient’s perception and may need to be addressed with a multidisciplinary approach. Maladaptive cognitive responses can lead to a negative illness perception and impact patient beliefs and concerns over treatment, as well as nonadherence. An underlying inflammatory component in affective disorders has been examined, though whether and how it may interact mechanistically in PsA warrants interest. Cognitive behavioral therapy represents a nonpharmacological treatment modality that can be combined with cytokine-targeted therapy to address both somatic and psychological complaints. Future directions for research include: (1) Elucidating nonspecific manifestations (e.g., subclinical stage, differential with functional syndromes) of PsA and how they impact diagnosis and management; (2) characterizing immune-mediated components of mood disorders in PsA; and (3) whether a bidirectional approach with abrogating inflammation and psychotherapeutic support leads to improved outcomes.
Does eight-plate epiphysiodesis of the proximal tibia in treating angular deformity create intra-articular deformity?

AIMS Eight-plates are used to correct varus-valgus deformity (VVD) or limb-length discrepancy (LLD) in children and adolescents. It was reported that these implants might create a bony deformity within the knee joint by change of the roof angle (RA) after epiphysiodesis of the proximal tibia following a radiological assessment limited to anteroposterior (AP) radiographs. The aim of this study was to analyze the RA, complemented with lateral knee radiographs, with focus on the tibial slope (TS) and the degree of deformity correction. METHODS A retrospective, single-centre study was conducted. The treatment group (n = 64 knees in 44 patients) was subclassified according to the implant location in two groups: 1) medial hemiepiphysiodesis; and 2) lateral hemiepiphysiodesis. A third control group consisted of 25 untreated knees. The limb axes and RA were measured on long standing AP leg radiographs. Lateral radiographs of 40 knees were available for TS analysis. The mean age of the patients was 10.6 years (4 to 15) in the treatment group and 8.4 years (4 to 14) in the control group. Implants were removed after a mean 1.2 years (0.5 to 3). RESULTS No significant differences in RA (p = 0.174) and TS (p = 0.787) were observed. The limb axes were significantly corrected in patients with VVD (p < 0.001). The change in tibial slope (∆TS) did not correlate (r = -0.026; p = 0.885) to the plate's position on the physis when assessed by lateral radiographs. CONCLUSION We were not able to confirm the reported change in the bony morphology of the proximal tibia on AP radiographs in our patient population. In addition, no significant change in TS was detected on the lateral radiographs. A significant correction of the VVD in the lower limb axes was evident. Position of the implant did not correlate with TS change. Therefore, eight-plate epiphysiodesis is a safe and effective procedure for correcting VVD in children without disturbing the knee joint morphology. Cite this article: Bone Joint J 2020;102-B(10):1412-1418.
Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data

Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies.
Stroke as a Potential Complication of COVID-19-Associated Coagulopathy: A Narrative and Systematic Review of the Literature

Coronavirus disease 2019 (COVID-19) is the most overwhelming medical threat of the past few decades. The infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause serious illness leading to respiratory insufficiency, and, in severely ill patients, it can progress to multiple organ failure leading to death. It has been noted from the earliest reports that the disease influences the hemostasis system and a hallmark of severe infection is elevated D-dimer levels. The profound coagulation changes in COVID-19 seem to be linked to inflammation-related events and severe endothelial cell injury. Besides the high incidence of venous thromboembolic events in SARS-CoV-2 infections, arterial events, including cerebrovascular events, were found to be associated with the disease. In this review, we aimed to summarize the available literature on COVID-19-associated coagulopathy and thrombosis. Furthermore, we performed a systematic search of the literature to identify the characteristics of stroke in COVID-19. Our findings showed that acute ischemic stroke (AIS) is the most frequent type of stroke occurring in infected patients. In most cases, stroke was severe (median NIHSS:16) and most of the patients had one or more vascular risk factors. Laboratory findings in AIS patients were consistent with COVID-19-associated coagulopathy, and elevated D-dimer levels were the most common finding. The outcome was unfavorable in most cases, as a large proportion of the reported patients died or remained bedridden. Limited data are available as yet on outcomes after acute vascular interventions in COVID-19 patients. In the future, well-designed studies are needed to better understand the risk of stroke in COVID-19, to optimize treatment, and to improve stroke care.
Rare broncho-pulmonary arterial fistula in a healthy 9-year-old girl

A 9-year-old previously well girl presented with multiple episodes of large volume haemoptysis and right sided consolidation. She continued to have haemoptysis despite intravenous antibiotics. CT chest suggested a right mainstem endobronchial lesion; this was not seen on bronchoscopy where an extensive blood clot was removed. Distal flexible bronchoscopy could not identify the source of bleeding. CT angiogram revealed a broncho-pulmonary arterial fistula, a rare cause of haemoptysis in children. Endovascular embolisation resulted in short-term symptom resolution; however, haemoptysis recurred months later, leading to re-embolisation. This case highlights a stepwise approach to the workup of large volume haemoptysis.
Small intestinal metabolism is central to whole-body insulin resistance

Objective To assess the role of jejunum in insulin resistance in humans and in experimental animals. Design Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model. We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop. In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling. Results Whole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017). Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity. A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans. Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans. Conclusion Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity. Trial registration number NCT03111953.
Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Simple Summary Colorectal carcinomas from patients with Lynch syndrome (LS) due to EPCAM deletions show loss of MSH2 expression. The aim of our study was to evaluate the usefulness of EPCAM expression in identifying carriers of EPCAM deletion among patients with MSH2-negative lesions. MSH2 and EPCAM immunohistochemistry was performed in a large series of lesions (190) composed of malignant and benign neoplasms as well as precursor lesions of different organs from 71 patients with suspected LS due to MSH2 alterations. Germ-line analysis confirmed LS in 68 patients due to MSH2 mutations (53) and EPCAM deletions (15). Among colorectal lesions with lack of MSH2 expression, only 17 were EPCAM-negative and belonged to patients with EPCAM deletions. We confirm that loss of EPCAM expression identifies EPCAM deletion carriers with 100% specificity and we recommend adding EPCAM IHC to the algorithm of MSH2-negative colorectal neoplasia. Abstract The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3′-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3′-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3′-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.
Cerebrospinal Fluid Levels of Prodynorphin‐Derived Peptides are Decreased in Huntington's Disease

Huntingtonʼs disease (HD) is a devastating neurodegenerative disorder characterized by a selective loss of striatal medium spiny projection neurons (MSNs). Prodynorphin (PDYN) is enriched in a subpopulation of striatal MSNs. Postmortem brains of HD patients and rodent models have been demonstrated to have reduced levels of PDYN transcripts and the neuropeptide dynorphin.
Analysis of the Genetic Structure of a Natural Population of Anastrepha fraterculus (Diptera: Tephritidae)

The South American fruit fly Anastrepha fraterculus (Wiedemann) is distributed from Mexico to northern and central Argentina. It is a polyphagous species using diverse fruit from wild and cultivated tree or shrub species as feeding and breeding sites. During larval stages, the environment is discontinuous, because the larvae are restricted to the fruit where their eggs were laid. This population structure should profoundly influence the distribution of genetic variation and the modes of action of adaptive mechanisms. During the adult stage, in contrast, the population is not structured. In the current work we analyze the genetic structure in an Argentine population (Yuto) among attacked fruits at 4 enzyme loci. The results differed from the expected for a random mating population in the genotypic frequency distribution, the effective inbreeding coefficients, and the correlation between allelic and nonallelic variant frequencies. The most plausible explanation is that populations of this species may include heterogeneous groups of individuals having different origins as the species undergoes host shifts throughout the year.
Effect of temperature on biology of Callosobruchus maculatus (F.).

Callosobruchus maculatus (F.) was reared on four varieties (Bio L 212 Ratan, Nirmal B-1, WBK-14-7 and WBK-13-1) of khesari seeds at four constant temperatures (20, 25, 30 and 35°C) and a relative humidity of 70 ± 5% with a photoperiod of 14L: 10D. C. maculatus could not complete development at 20°C. The developmental time from egg hatching to adult emergence of C. maculatus except WBK-147 seed was shortest at 30°C and longest at 25°C; whereas WBK-14-7 fed insects had a faster developmental time at 30 and 35°C. Further, developmental time of C. maculatus was fastest on Bio L 212 Ratan at 30°C, suggesting that greater damage would be due to repetition of several generations annually. Longevity of males and females was found to be shortest at 35°C and longest at 20°C. Fecundity was maximum at 30°C over an incubation period of 6.27 - 7.08 days; whereas this was minimum at 20°C, but failed to hatch.