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Abstract Background Kinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations. Methods We investigated the pan-cancer genomic landscape of BRAF class III mutations in 376,302 patients. Patients had comprehensive genomic profiling either by FoundationOne® or FoundationOne®CDx from formalin-fixed, paraffin embedded tissue biopsies. 2 patient cases that harbored BRAF class III mutations who demonstrated dramatic response to anti-EGFR treatment were presented. Results BRAF class III mutations are likely to co-occur with RAF1, NRAS and HRAS alterations, while concomitant KRAS alterations were rare. Moreover, we found that alterations that predict resistance to anti-EGFR agents were significantly less common in tumors harboring BRAF class III mutations, which is of great importance as anti-EGFR therapies are a potential targeted treatment option in these tumors. Discussion Our findings suggest a heterogenous interplay of oncogenic alterations in BRAF class III mutated tumors and have important implications for the molecular mechanisms of carcinogenesis while revealing potential therapeutic vulnerabilities. Highlights Tumors harboring BRAF class III (BRAF vIII) mutations comprise a novel subset with distinct genomic heterogeneity. BRAF vIII mutations may sensitize tumors to anti-EGFR treatments. BRAF vIII alterations show significantly less co-occurrence with alterations that predict resistance to anti-EGFR agents. Rare tumors with limited therapy options should be screened for BRAF vIII mutations as they may benefit from anti-EGFR agents.

Abstract We demonstrate two general classes of magnetophoretic transistors, called the “trap” and the “repel-and-collect” transistors, capable of switching single magnetically labeled cells and magnetic particles between different paths in a microfluidic chamber. Compared with prior work on magnetophoretic transistors operating in a two-dimensional in-plane rotating field, the use of a tri-axial magnetic field has the fundamental advantages of preventing particle cluster formation and better syncing of single particles with the general operating clock. We use finite element methods to investigate the energy distribution on the chip surface and to predict the particle behavior at various device geometries. We then fabricate the proposed transistors and compare the experimental results with the simulation predictions. We found that with gate electrical currents of ~ 40 mA for a transistor with proper geometry, complete switching of magnetic particles with diameters in the range of 8–15 μm is achieved. We show that the device is reliable and works well at different magnetic field strengths (50–100 Oe) and frequencies (0.05–0.5 Hz). We also employed an image processing code with a trained convolutional neural network to automate the proposed transistors for identifying and sorting particles with various sizes and magnetic susceptibilities with accuracies higher than 98%. The proposed transistors can be used in designing novel magnetophoretic circuits for important applications in biomedical microdevices and single-cell biology.

Abstract When studying the working memory (WM), the ‘slot model’ and the ‘resource model’ are two main theories used to describe how information retention occurs. The slot model shows that WM capacity consists of a certain number of predefined slots available for information storage. This theory explains that there is a binary condition during information recall in which information is either wholly maintained within a slot or forgotten. The resource model has a resolution-based approach, suggesting a continuous resource able to be distributed among a number of items in WM capacity. Recently hybrid models have been introduced, suggesting that WM may not strictly conform to only one model. Accordingly, to understand the relationship between two of the most widely used paradigms in WM evaluation, we implemented a correlational assessment in two different psychophysics tasks, an analog recall paradigm with sequential bar presentation and a delayed match-to-sample (DMS) task with checkerboard stimuli. Our study revealed significant correlations between WM performance in the DMS task and recall error, precision, and sources of errors in the sequential paradigm. Overall, the findings emphasize the importance of considering both tasks in understanding WM processes, as they shed light on the debate between the slot and resource models by revealing overlapping elements in both theories and the tasks used to evaluate WM capacity.

Foodborne diseases are a significant global public health concern due to their high prevalence, mortality, and economic losses. The aim of this study was to conduct a systematic review of identified foodborne pathogens and outbreaks in Iran over the past 23 years to provide an overview of the risk assessment and prevention approaches in the country. Using appropriate keywords and searching major databases, such as ScienceDirect, Scopus, PubMed, Google Scholar, and the Iranian Scientific Knowledge Database, we initially identified 4,740 articles. Finally, 328 articles were selected for evaluation. Among these articles, publications on Salmonella, Staphylococcus aureus, and Listeria were the most numerous. Poultry meat was found to be the main source of major foodborne pathogens in Iran, including Campylobacter (46.21%), Listeria monocytogenes (38.45), Salmonella (24.83%), and Yersinia enterocolitica (16.81%). Given the high prevalence of foodborne bacteria in Iranian foods, it is crucial to implement effective control measures to reduce the risk and burden of foodborne diseases. In particular, poultry meat, which poses a high risk for the occurrence of foodborne diseases in Iran, should be subjected to further risk assessment and control measures throughout the food chain.

There is currently no effective treatment strategy for recurrent/metastatic adenoid cystic carcinoma (R/M ACC). Furthermore, recent single-agent and combination immunotherapy trials have failed in unselected ACC cohorts, unlike non-ACC salivary gland cancers. Genomic profiling revealed no actionable targets but NOTCH1 and KDM6A frameshift and CTCF splice site mutations (no MYB/L fusion) with a low tumor mutational burden (TMB), microsatellite stable (MSS) and negative programmed death ligand 1 (PD-L1) were observed. We recommended an anti-programmed cell death protein 1 (anti-PD-1) plus anti-Cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) combination based on TMB 2-fold greater-than-median TMB in ACC, tumor harboring multiple immunogenic frameshift or splice site mutations, and PD-L1 negativity. Accordingly, we achieved a complete response in a radiotherapy (RT) and chemotherapy (CT)-refractory patient with locally recurrent lacrimal gland (LG) ACC and lung metastasis following personalized immunotherapy in combination with integrative therapeutics. Therefore, it is crucial to assess not only conventional immune biomarkers but also patient-specific parameters, especially in “immune-cold” cancer types.

Abstract Background In goat kids, choosing the appropriate age to administer the first dose of goat pox disease (GTP) vaccine requires knowing when maternal antibody decline concentrations. Objective Determine the persistence of maternal antibodies against goat pox virus (GTPV) in goat kids. Animals Twenty Saanen goat kids from birth to 120 days old. Methods In 2 groups, including: control (receiving colostrum from nonvaccinated does) and treatment (receiving colostrum from vaccinated does). On zero, 3, 7, 14, 21, 28, 42, 56, 70, 100 and 120 days after the birth, virus neutralization test was used to measure the serum concentration of antibodies against GTPV. Results At the age of 56 days, the first seronegative goat kids (n = 2) were recorded in the treatment group. At the age of 120 days, all the goat kids in the treatment group were seronegative. The average virus neutralization index (VNI) of the goat kids became negative at the age of 100 to 120 days. All goat kids in the control group were negative at all times. Conclusions and Clinical Importance One hundred to 120 days of the age seems to be the time to administer the first GTP vaccine in the goat kids with passive immunity against goat pox.

Objectives: The present study compared respiratory parameters between the two methods of airwayestablishment, ETT and LMA, for patients scheduled for orthopedic surgery with general anesthesia.Methods: This randomized double-blinded clinical trial was conducted on patients scheduled for electiveorthopedic surgery under general anesthesia, in Bandar Abbas, Iran, from January 2021 to December 2021.Using a random allocation table, the study participants were randomly divided into two groups, to employeither ETT (n=48) or LMA insertion (n=48). The study’s ultimate goal was to assess the respiratory parametersin 1, 3, 5, 10, and 15 minutes following intubation.Results: At all-time points, the average of peak airway pressure (P peak) and P plateau parameters in theETT group was much higher than the EMA group (p0.05).Conclusion: In terms of arterial oxygen saturation stability and at the same time providing respiratory dynamiccompliance, the LMA device outperformed the ETT.

Summary: Introduction: Multiple Sclerosis (MS) is an immune-mediated central nervous system disorder, often accompanied by fatigue, which can be an initial symptom. Cocoa, rich in antioxidants like flavonoids, has previously reduced fatigue in chronic fatigue syndrome patients. This study aimed to assess cocoa's impact on fatigue in patients with relapsing-remitting MS (RRMS). Methods: This study was a double-blind, parallel placebo-controlled trial in patients with RRMS. A total number of 60 patients entered the study and were divided into intervention and control groups. The intervention group consumed 25 grams of cocoa daily, split into two 12.5-gram sachets, while the placebo group received 2.5 grams daily. Modified fatigue impact scale (MFIS) and Fatigue severity scale (FSS) questionnaires were filled at baseline, week 4, and week 8. Results: No significant changes were observed in FSS (P = 0.90) and MFIS (P = 0.37) during the interventions. No significant differences were observed in the questionnaire score changes between the two groups, except for the FSS decrease in the second four weeks (P < 0.05). FSS and MFIS were significantly correlated during different assessment times (P < 0.05). Both MFIS and FSS scores were correlated with Beck's depression inventory score. Conclusions: We indicated that FSS changed significantly after cocoa consumption in patients with RRMS. The FSS score of the cocoa group continued to decrease during the subsequent four weeks, unlike the placebo group. It appears that cocoa primarily affects physical fatigue rather than psychosocial or cognitive fatigue. While these results align with some prior studies, further research on larger populations is necessary to confirm these findings.

Working memory plays an important role in learning since it serves as the buffer between past sensations and future behavior, making it essential to understand not only how we encode and recall sensory information in memory but also how we plan for its upcoming use. This study examined the effect of working memory training on vocabulary recall and retention of Iranian EFL learners using the dual N-back task technique. N-back requires the individual to remember an item that was presented a certain number of items previously. To this end, 50 EFL learners were randomly assigned to the experimental (n = 25) and control (n = 25) groups. The participants were taught 100 English words in 20 sessions. In each session, the experimental group also received a dual n-back task. After the treatment, immediate and delayed vocabulary posttests were administered. The obtained data were analyzed through two-way repeated-measures ANOVA and independent samples "t"-tests. The results showed that the experimental group outperformed the control group in target words' recall and retention.

Breast cancer (BC) is the leading cause of cancer-related mortality among women, and hormone receptor (HR)-positive subtype makes up the majority of all cases. The standard of care in HR + /HER2 − metastatic BC (MBC) is endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). ESR1 mutations could impair the clinical efficacy of the ETs. Similarly, PIK3CA mutations may serve as a negative prognostic marker. Furthermore, MBC is challenging to treat despite new drug approvals. Our patient received multiple lines of ET ± CDK4/6i and chemotherapy but persistently progressed after each or stopped the treatment due to adverse events. Here we showed for the first time that an all-oral combination of elacestrant plus alpelisib was feasible, tolerable, and clinically active in an ESR1 and PIK3CA co-mutated and heavily pretreated patient. We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

Triphalangeal thumb is a rare congenital anomaly especially in Asian population. Traditional treatments depend on the type of deformity and the presence of concomitant anomalies and include either excision in addition to the ligament reconstruction or fusion and shortening osteotomy. Instability and stiffness are the major concerns following the traditional techniques. In this study, we report a case of right triphalangeal thumb with a small delta phalanx in a nine-year-old boy that was treated by proximal phalanx radial closed wedge osteotomy without delta phalanx resection and intracapsular dissection. The angular deformity and the appearance of the thumb was corrected by this simple procedure without resulting in instability and stiffness in the interphalangeal joint.

Abstract The objective of this study was to synthesize a novel antibacterial and anticancer nanoformulation using aloe vera-derived carbon quantum dots (Cdot) and chromium-doped alumina nanoparticles (Al2O3:Cr/Cdot NPs) via a sol–gel method. X-ray diffraction (XRD) analysis confirmed crystalline NPs with a size range of 10–12 nm, while energy-dispersive X-ray spectroscopy (EDS) revealed their elemental composition without impurities. Fourier-transform infrared spectroscopy (FT-IR) indicated strong interactions between Cdot and Al2O3:Cr NPs, forming a robust heterostructure. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images provided visual confirmation of monodisperse, spherical NPs, ensuring uniformity for further applications. Evaluation of reactive oxygen species (ROS) demonstrated superior generation of singlet oxygen and hydroxyl radicals by Al2O3:Cr/Cdot NPs, essential for photodynamic therapy. Minimum inhibitory concentration (MIC) tests revealed potent antibacterial activity against drug-resistant bacteria, inhibiting biofilm formation by 89% and 95% for MRSA and P. aeruginosa PAO1, respectively. Furthermore, the anticancer activity of Al2O3:Cr/Cdot NPs was assessed using C26 cells, demonstrating enhanced cytotoxicity upon UVA exposure. The NPs exhibited an inhibitory concentration (IC50) of 20 μg/mL without UVA exposure, decreasing to 10 μg/mL with UVA exposure, highlighting the synergistic effect of UVA light in enhancing cytotoxicity. Overall, these findings underscore the significant potential of Al2O3:Cr/Cdot NPs as multifunctional agents for addressing drug-resistant bacteria and advancing cancer therapy, offering promising avenues for nanomedicine research and development.

Abstract Aromatic compounds are known anti-amyloid aggregates. Their effect on amorphous aggregates of proteins is, however, less studied. We chose aromatic amino acids Trp, Tyr, and Phe, as well as another known stabilizer (i.e. Arg), as potential compatible solvents to be tested on Bacillus amyloliquefaciens alpha-amylase (BAA). Among these additives, Phe was the only one to be effective on the thermal inactivation and amorphous aggregation of BAA, while preserving its intrinsic activity. A concentration of 50 mM Phe was used to test its potential in counteracting the deleterious effect of BAA amorphous aggregates in vivo. After 21 days of daily subcutaneous injections of the native enzyme to mice, amorphous aggregates of BAA, as well as aggregates produced in presence of 50 mM Phe, the tissues located at the site of injection were studied histologically. Amorphous aggregates caused an increase in macrophages and lipid droplets. Serum levels of IL6 and TNF-α were also accordingly elevated and indicative of an inflammation state. Aggregates also resulted into increased levels of glucose, triglycerides and cholesterol, as well as liver enzymes SGOT and SGPT. On the other hand, the presence of Phe prevented this exacerbated inflammatory state and the subsequent impairment of biochemical parameters. In conclusion, Phe is an interesting compound for both stabilizing proteins and counteracting the pathological effect of amorphous aggregates.

BackgroundPhthalate exposure in pregnancy is typically estimated using maternal urinary phthalate metabolite levels. Our aim was to evaluate the association of urinary and placental tissue phthalates, and to explore the role of maternal and pregnancy characteristics that may bias estimates.MethodsFifty pregnancies were selected from the CANDLE Study, recruited from 2006 to 2011 in Tennessee. Linear models were used to estimate associations of urinary phthalates (2nd, 3rd trimesters) and placental tissue phthalates (birth). Potential confounders and modifiers were evaluated in categories: temporality (time between urine and placenta sample), fetal sex, demographics, social advantage, reproductive history, medication use, nutrition and adiposity. Molar and quantile normalized phthalates were calculated to facilitate comparison of placental and urinary levels.ResultsMetabolites detectable in >80% of both urine and placental samples were MEP, MnBP, MBzP, MECPP, MEOHP, MEHHP, and MEHP. MEP was most abundant in urine (geometric mean [GM] 7.00 ×102 nmol/l) and in placental tissue (GM 2.56 ×104 nmol/l). MEHP was the least abundant in urine (GM 5.32 ×101 nmol/l) and second most abundant in placental tissue (2.04 ×104 nmol/l). In aggregate, MEHP differed the most between urine and placenta (2.21 log units), and MEHHP differed the least (0.07 log units). MECPP was positively associated between urine and placenta (regression coefficient: 0.31 95% CI 0.09, 0.53). Other urine-placenta metabolite associations were modified by measures of social advantage, reproductive history, medication use, and adiposity.ConclusionPhthalates were ubiquitous in 50 full-term placental samples, as has already been shown in maternal urine. MEP and MEHP were the most abundant. Measurement and comparison of urinary and placental phthalates can advance knowledge on phthalate toxicity in pregnancy and provide insight into the validity and accuracy of relying on maternal urinary concentrations to estimate placental exposures.Impact statementThis is the first report of correlations/associations of urinary and placental tissue phthalates in human pregnancy. Epidemiologists have relied exclusively on maternal urinary phthalate metabolite concentrations to assess exposures in pregnant women and risk to their fetuses. Even though it has not yet been confirmed empirically, it is widely assumed that urinary concentrations are strongly and positively correlated with placental and fetal levels. Our data suggest that may not be the case, and these associations may vary by phthalate metabolite and associations may be modified by measures of social advantage, reproductive history, medication use, and adiposity.