Notes

Iranian medical school aboard involving trustees' challenges utilized: Any qualitative review.
Cancer is one of the major causes of death in the world and its global burden is expected to continue increasing. In several types of cancers, reactive oxygen species (ROS) have been extensively linked to carcinogenesis and cancer progression. However, studies have reported conflicting evidence regarding the role of ROS in cancer, mostly dependent on the cancer type or the step of the tumorigenic process. We review recent studies describing diverse aspects of the interplay of ROS with cancer in the different stages of cancer progression, with a special focus on their role in carcinogenesis, their importance for cancer cell signaling and their relationship to the most prevalent cancer risk factors.Neurons and glial cells are endowed with membranes that express a rich repertoire of ion channels, transporters, and receptors. The constant flux of ions across the neuronal and glial membranes results in voltage fluctuations that can be recorded from the extracellular matrix. The high frequency components of this voltage signal contain information about the spiking activity, reflecting the output from the neurons surrounding the recording location. The low frequency components of the signal, referred to as the local field potential (LFP), have been traditionally thought to provide information about the synaptic inputs that impinge on the large dendritic trees of various neurons. In this review, we discuss recent computational and experimental studies pointing to a critical role of several active dendritic mechanisms that can influence the genesis and the location-dependent spectro-temporal dynamics of LFPs, spanning different brain regions. We strongly emphasize the need to account for the several fast and slow dendritic events and associated active mechanisms--including gradients in their expression profiles, inter- and intra-cellular spatio-temporal interactions spanning neurons and glia, heterogeneities and degeneracy across scales, neuromodulatory influences, and activity-dependent plasticity-towards gaining important insights about the origins of LFP under different behavioral states in health and disease. We provide simple but essential guidelines on how to model LFPs taking into account these dendritic mechanisms, with detailed methodology on how to account for various heterogeneities and electrophysiological properties of neurons and synapses while studying LFPs.Among the hypomyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) is a representative disorder. The disease is caused by different types of PLP1 mutations, among which PLP1 duplication accounts for ∼70% of the mutations. Previous studies have shown that PLP1 duplications lead to PLP1 retention in the endoplasmic reticulum (ER); in parallel, recent studies have demonstrated that PLP1 duplication can also lead to mitochondrial dysfunction. As such, the respective roles and interactions of the ER and mitochondria in the pathogenesis of PLP1 duplication are not clear. In both PLP1 patients' and healthy fibroblasts, we measured mitochondrial respiration with a Seahorse XF Extracellular Analyzer and examined the interactions between the ER and mitochondria with super-resolution microscopy (spinning-disc pinhole-based structured illumination microscopy, SD-SIM). For the first time, we demonstrated that PLP1 duplication mutants had closer ER-mitochondrion interfaces mediated through structural and morphological changes in both the ER and mitochondria-associated membranes (MAMs). These changes in both the ER and mitochondria then led to mitochondrial dysfunction, as reported previously. This work highlights the roles of MAMs in bridging PLP1 expression in the ER and pathogenic dysfunction in mitochondria, providing novel insight into the pathogenicity of mitochondrial dysfunction resulting from PLP1 duplication. These findings suggest that interactions between the ER and mitochondria may underlie pathogenic mechanisms of hypomyelinating leukodystrophies diseases at the organelle level.
In high-grade soft-tissue sarcomas (STS) the standard of care encompasses multimodal therapy regimens. While there is a growing body of evidence for prognostic pretreatment radiomic models, we hypothesized that temporal changes in radiomic features following neoadjuvant treatment ("delta-radiomics") may be able to predict the pathological complete response (pCR).

MRI scans (T1-weighted with fat-saturation and contrast-enhancement (T1FSGd) and T2-weighted with fat-saturation (T2FS)) of patients with STS of the extremities and trunk treated with neoadjuvant therapy were gathered from two independent institutions (training 103, external testing 53 patients). pCR was defined as < 5% viable cells. After segmentation and preprocessing, 105 radiomic features were extracted. Delta-radiomic features were calculated by subtraction of features derived from MRI scans obtained before and after neoadjuvant therapy. After feature reduction, machine learning modeling was performed in 100 iterations of 3-fold nested crs may one day function as a biomarker for personalized treatment adaptations.We analyzed CTCAE adverse events of sequential Carbon Ion radiotherapy (CIRT) and immune checkpoint inhibitors (ICIs) in advanced melanoma patients. The frequencies of early and late adverse events (AEs) were 100% and 82% of patients, respectively. The frequency of G3+ AEs was in line with the literature.
Cranial neuropathy is a common presenting symptom of advanced T4 nasopharyngeal carcinoma (NPC). Data on neurological outcomes after modern intensity-modulated radiotherapy (IMRT) and chemotherapy are scarce.

Case records of consecutive T4 NPC patients who received definitive IMRT in two tertiary oncology centers in 2004-2019 were reviewed. Patterns of cranial neuropathies at disease presentation were recorded. Time to neurological recovery and the rate of subsequent re-palsy were estimated by the Kaplan-Meier method. Clinical predictors were analyzed using multivariable Cox regression.

During the study period, 257 T4 NPC patients presented with 504 individual cranial neuropathies. The median time from neuropathy onset to NPC diagnosis was two months (IQR, 1-4months). Cranial nerves (CN) VI (56.4%), V2 (47.9%), and V3 (29.2%) were most frequently involved. At a median follow-up of 6.4years, the crude partial and full recovery rates of neuropathies were 111 (22%) and 289 (57.3%), respectively. CN III, IV, and VI had the highest 5-year full recovery rate (72.7%), followed by CN V1-3 (60.3%), XII (48.6%), and II (18.2%) (p<0.001). buy MV1035 Positive smoking history, optic nerve involvement, and longer duration of neuropathy were independent negative predictors for neurological recovery. After full recovery, re-palsy was observed in 6.9% (20/289) of the nerves, 60% of which co-occurred with local NPC recurrences.

Durable recovery of most cranial neuropathies in advanced T4 NPC was observed in the era of modern IMRT and effective systemic chemotherapy. Both patient and disease factors affected the chance of neurological recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.
Durable recovery of most cranial neuropathies in advanced T4 NPC was observed in the era of modern IMRT and effective systemic chemotherapy. Both patient and disease factors affected the chance of neurological recovery. Re-palsy of recovered nerves should prompt careful evaluation for local recurrence.
To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LET
) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT).

Clinical plans of 50 SC patients consecutively treated before August 2018 with a local effect model-based optimization were recalculated with the modified microdosimetric kinetic RBE model (mMKM). Twenty-six patients were classified as progressive disease and the relapse volume was contoured on the corresponding follow-up diagnostic sequence. The remaining 24 patients populated the control group. Target prescription dose (D
), near-to-minimum- (D
) and near-to-maximum- (D
) doses were compared between the two cohorts in both RBE systems. LET
distribution was evaluated for in-field relapsed cases with respect to the control group.

Target D
and D
were respectively 10% and 18% lower than what we aimed at. Dosimetric evaluators showed no significant difference, in neither of the RBE frameworks, between relapsed and control sets. Half of the relapse volumes were located in a well-covered high dose region. On average, over these cases, median target LET
was significantly lower than the control cohort mean value (27 vs 30keV/μm). Most notably, the volume receiving dose from high-LET particles (>50keV/μm) lay substantially below recently reported data in the literature.

A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas.
A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas.
Positional verification during single fraction lung SBRT could increase confidence and reduce the chance of geographic miss. As planar 2DkV imaging during VMAT irradiation is already available on current linear accelerators, markerless tracking based on these images could offer widely available and low-cost verification. We evaluated treatment delivery data and template matching and triangulation for 3D-positional verification during free-breathing, single fraction (34Gy), 10 MV flattening-filter-free VMAT lung SBRT.

Tumor tracking based on kV imaging at 7 frames/second was performed during irradiation in 6 consecutive patients (7 lesions). Tumor characteristics, tracking ability, comparison of tracking displacements with CBCT-based shifts, tumor position relative to the PTV margin, and treatment times are reported.

For all 7 lesions combined, 3D tumor position could be determined for, on average, 71% (51-84%) of the total irradiation time. Visually estimated tracked and automated match +/- manually-corrected CBCT-derived displacements generally agreed within 1mm. During the tracked period, the longitudinal, lateral and vertical position of the tumor was within a 5mm/3mm PTV margin 95.5/85.3% of the time. The PTV was derived from the ITV including all tumor motion. The total time from first set-up imaging to end of the last arc was 18.3-31.4min (mean=23.4, SD=4.1).

3D positional verification during irradiation of small lung targets with limited motion, was feasible. However, tumor position could not be determined for on average 29% of the time. Improvements are needed. Margin reduction may be feasible. Imaging and delivery of a single 34Gy fraction was fast.
3D positional verification during irradiation of small lung targets with limited motion, was feasible. However, tumor position could not be determined for on average 29% of the time. Improvements are needed. Margin reduction may be feasible. Imaging and delivery of a single 34 Gy fraction was fast.
ST-segment elevation myocardial infarction (STEMI) patients are treated with dual antiplatelet therapy comprising aspirin and a P2Y
inhibitor. Clopidogrel is widely used in these patients in several areas worldwide, such as Middle East, but is associated to sub-optimal platelet inhibition in up to 1/3 of treated patients. We investigated a CYP2C19 genotype-guided strategy to select the optimal P2Y
inhibitor.

This prospective randomized clinical trial included STEMI patients. The standard-treatment group received clopidogrel, while the genotype-guided group were genotyped for CYP2C19 loss-of-function alleles and carriers were prescribed ticagrelor and noncarriers were prescribed clopidogrel. Primary outcome was a combined ischemic and bleeding outcome, comprising myocardial infarction, non-fatal stroke, cardiovascular death, or Platelet Inhibition and Patient Outcomes major bleeding one year after STEMI.

STEMI patients (755) were randomized into a genotype-guided- (383) and standard-treatment group (372).
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