Feasibility of the J-PET to monitor the range of therapeutic proton beams.

PURPOSE: The aim of this work is to investigate the feasibility of the Jagiellonian Positron Emission Tomography (J-PET) scanner for intra-treatment proton beam range monitoring. METHODS: The Monte Carlo simulation studies with GATE and PET image reconstruction with CASToR were performed in order to compare six J-PET scanner geometries. We simulated proton irradiation of a PMMA phantom with a Single Pencil Beam (SPB) and Spread-Out Bragg Peak (SOBP) of various ranges. The sensitivity and precision of each scanner were calculated, and considering the setup's cost-effectiveness, we indicated potentially optimal geometries for the J-PET scanner prototype dedicated to the proton beam range assessment. RESULTS: The investigations indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for clinical application. We found that the scanner sensitivity is of the order of 10-5 coincidences per primary proton, while the precision of the range assessment for both SPB and SOBP irradiation plans was found below 1 mm. Among the scanners with the same number of detector modules, the best results are found for the triple-layer dual-head geometry. The results indicate that the double-layer cylindrical and triple-layer double-head configurations are the most promising for the clinical application, CONCLUSIONS:: We performed simulation studies demonstrating that the feasibility of the J-PET detector for PET-based proton beam therapy range monitoring is possible with reasonable sensitivity and precision enabling its pre-clinical tests in the clinical proton therapy environment. Considering the sensitivity, precision and cost-effectiveness, the double-layer cylindrical and triple-layer dual-head J-PET geometry configurations seem promising for future clinical application.

miRNAs in the prognosis of triple-negative breast cancer: A review.

Triple-Negative Breast Cancer (TNBC) is a highly aggressive and invasive type of breast cancer (BC) with high mortality rate wherein effective target medicaments are lacking. It is a very heterogeneous group with several subtypes that account for 10-20% of cancer among women globally, being negative for three most important receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)), with an early and high recurrence resulting in poor survival rate. Therefore, a more thorough knowledge on carcinogenesis of TNBC is required for the development of personalized treatment options. miRNAs can either promote or suppress tumorigenesis and have been linked to a number of features of cancer progression, including proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition (EMT). Recent miRNA research shows that there is great potential for the development of novel biomarkers as they have emerged as drivers of tumorigenesis and provide opportunities to target various components involved in TNBC, thus helping to solve this difficult-to-treat disease. In this review, we summarize the most relevant miRNAs that play an essential role in TNBC biology. Their role with regard to molecular mechanisms underlying TNBC progression has been discussed, and their potential use as therapeutic or prognostic markers to unravel the intricacy of TNBC based on the pieces of evidence obtained from various works of literature has been briefly addressed.

Onco-Pathogen Mediated Cancer Progression and Associated Signaling Pathways in Cancer Development.

Infection with viruses, bacteria, and parasites are thought to be the underlying cause of about 8-17% of the world's cancer burden, i.e., approximately one in every five malignancies globally is caused by an infectious pathogen. Oncogenesis is thought to be aided by eleven major pathogens. It is crucial to identify microorganisms that potentially act as human carcinogens and to understand how exposure to such pathogens occur as well as the following carcinogenic pathways they induce. Gaining knowledge in this field will give important suggestions for effective pathogen-driven cancer care, control, and, ultimately, prevention. This review will mainly focus on the major onco-pathogens and the types of cancer caused by them. It will also discuss the major pathways which, when altered, lead to the progression of these cancers.

Unc13A dynamically stabilizes vesicle priming at synaptic release sites for short-term facilitation and homeostatic potentiation.

Presynaptic plasticity adjusts neurotransmitter (NT) liberation. Short-term facilitation (STF) tunes synapses to millisecond repetitive activation, while presynaptic homeostatic potentiation (PHP) of NT release stabilizes transmission over minutes. Despite different timescales of STF and PHP, our analysis of Drosophila neuromuscular junctions reveals functional overlap and shared molecular dependence on the release-site protein Unc13A. Mutating Unc13A's calmodulin binding domain (CaM-domain) increases baseline transmission while blocking STF and PHP. Mathematical modeling suggests that Ca2+/calmodulin/Unc13A interaction plastically stabilizes vesicle priming at release sites and that CaM-domain mutation causes constitutive stabilization, thereby blocking plasticity. Labeling the functionally essential Unc13A MUN domain reveals higher STED microscopy signals closer to release sites following CaM-domain mutation. Acute phorbol ester treatment similarly enhances NT release and blocks STF/PHP in synapses expressing wild-type Unc13A, while CaM-domain mutation occludes this, indicating common downstream effects. Thus, Unc13A regulatory domains integrate signals across timescales to switch release-site participation for synaptic plasticity.

Advances in the Lung Cancer Immunotherapy Approaches.

Despite the progress in the comprehension of LC progression, risk, immunologic control, and treatment choices, it is still the primary cause of cancer-related death. LC cells possess a very low and heterogeneous antigenicity, which allows them to passively evade the anticancer defense of the immune system by educating cytotoxic lymphocytes (CTLs), tumor-infiltrating lymphocytes (TILs), regulatory T cells (Treg), immune checkpoint inhibitors (ICIs), and myeloid-derived suppressor cells (MDSCs). Though ICIs are an important candidate in first-line therapy, consolidation therapy, adjuvant therapy, and other combination therapies involving traditional therapies, the need for new predictive immunotherapy biomarkers remains. Furthermore, ICI-induced resistance after an initial response makes it vital to seek and exploit new targets to benefit greatly from immunotherapy. As ICIs, tumor mutation burden (TMB), and microsatellite instability (MSI) are not ideal LC predictive markers, a multi-parameter analysis of the immune system considering tumor, stroma, and beyond can be the future-oriented predictive marker. The optimal patient selection with a proper adjuvant agent in immunotherapy approaches needs to be still revised. Here, we summarize advances in LC immunotherapy approaches with their clinical and preclinical trials considering cancer models and vaccines and the potential of employing immunology to predict immunotherapy effectiveness in cancer patients and address the viewpoints on future directions. We conclude that the field of lung cancer therapeutics can benefit from the use of combination strategies but with comprehension of their limitations and improvements.

Balance Assessment of Children with Sensorineural Hearing Loss.

This study aimed to assess the balance function in children with sensorineural hearing loss (SNHL) using different tests to assess vestibulospinal pathway and tests to assess vestibular system and to compare the result obtained with those of children with normal hearing sensitivity. Detailed balance assessment was done for 15 children with severe to profound SNHL and 15 children with normal hearing sensitivity in the age range of 6-10 years. The audiological evaluation included pure-tone audiometry, speech audiometry, immittance evaluation, otoacoustic emission, vestibular evoked myogenic potential (cervical VEMP and ocular VEMP), and tests to assess vestibulospinal pathway and cerebellar function, such as Romberg test, Fukuda stepping test, Tandem gait test, and Finger-to-nose test. cVEMP and oVEMP were absent in 8 ears (27%) of a total of 30 ears with SNHL. Statistical analysis shows no significant difference between latency and amplitude of cVEMP peaks and latency of oVEMP peaks across groups. Significant reduction of oVEMP peaks amplitude was seen in children with SNHL compared to children with normal hearing. Fukuda stepping test showed an abnormal response in 2 children with SNHL (13%) and one child could not perform tandem gait test (7%). Children with SNHL showed an evident abnormality on the balance assessment test results. The abnormal function of the vestibular system and the vestibulospinal pathway can compromise the child's motor development and thus needs investigation early in life.