OBJECTIVE: To investigate the potential of virtual contrast-enhanced MRI (VCE-MRI) for gross-tumor-volume (GTV) delineation of nasopharyngeal carcinoma (NPC) using multi-institutional data.
METHODS: This study retrospectively retrieved T1-weighted (T1w), T2-weighted (T2w) MRI, gadolinium-based contrast-enhanced MRI (CE-MRI) and planning CT of 348 biopsy-proven NPC patients from three oncology centers. A multimodality-guided synergistic neural network (MMgSN-Net) was trained using 288 patients to leverage complementary features in T1w and T2w MRI for VCE-MRI synthesis, which was independently evaluated using 60 patients. Three board-certified radiation oncologists and two medical physicists participated in clinical evaluations in three aspects: image quality assessment of the synthetic VCE-MRI, VCE-MRI in assisting target volume delineation, and effectiveness of VCE-MRI-based contours in treatment planning. The image quality assessment includes distinguishability between VCE-MRI and CE-MRI, clarity of tumor-to-normal tissue interface and veracity of contrast enhancement in tumor invasion risk areas. Primary tumor delineation and treatment planning were manually performed by radiation oncologists and medical physicists, respectively.
RESULTS: The mean accuracy to distinguish VCE-MRI from CE-MRI was 31.67%; no significant difference was observed in the clarity of tumor-to-normal tissue interface between VCE-MRI and CE-MRI; for the veracity of contrast enhancement in tumor invasion risk areas, an accuracy of 85.8% was obtained. The image quality assessment results suggest that the image quality of VCE-MRI is highly similar to real CE-MRI. The mean dosimetric difference of planning target volumes were less than 1Gy.
CONCLUSIONS: The VCE-MRI is highly promising to replace the use of gadolinium-based CE-MRI in tumor delineation of NPC patients.

OBJECTIVE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials.
METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined \"EBV response\" as 3 consecutive timepoints of load below 50% of baseline, and \"EBV progression\" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples.
RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS.
CONCLUSIONS: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.

This study aimed to investigate whether the RapidPlan (RP) model configured by volumetric modulated arc therapy (VMAT) plans of nasopharyngeal carcinoma (NPC) could be used to assist in the optimization of HT plans and improve their quality. An RP model was trained using 100 clinically accepted VMAT plans of NPC patients. The predicted dose constraints of the VMAT trained RP model were used to reoptimize 25 consecutive clinically accepted HT plans (HT_clinical) and perform new VMAT plans based on the same computed topography (CT). The dosimetric quality of the reoptimized HT plans (HT_reoptimized), HT_clinical, and VMAT group were compared. The minimum dose encompassing 2% target (D2%), the minimum dose encompassing 98% target (D98%), homogeneity index (HI) and conformity index (CI) were similar for most targets between the HT_clinical and HT_reoptimized plans, although certain targets in the HT_reoptimized plans had higher D2% and HI and lower D98%. The HT_reoptimized plans outperformed the HT_clinical plans in the Dmax and D1cc of the spinal cord, V40Gy of the left temporal lobe, Dmean and V30Gy of the oral cavity, Dmean of the larynx and thyroid, and the differences were statistically significant. HT plans had higher CI and HI than VMAT plans. HT plans outperformed VMAT plans in the Dmax of the spinal cord and lenses, V30Gy of the oral cavity and parotids, and V40Gy of the temporal lobes, but underperformed in the Dmax and D1cc of the brainstem, D1cc of the spinal cord and Dmean of the oral cavity. The VMAT-based RP model can be used to assist in the planning of HT plans and improve the dosimetry quality of HT plans.

Genome organization can regulate gene expression and promote cell fate transitions. The differentiation of germline stem cells (GSCs) to oocytes in Drosophila involves changes in genome organization mediated by heterochromatin and the nuclear pore complex (NPC). Heterochromatin represses germ cell genes during differentiation, and NPCs anchor these silenced genes to the nuclear periphery, maintaining silencing to allow for oocyte development. Surprisingly, we found that genome organization also contributes to NPC formation, mediated by the transcription factor Stonewall (Stwl). As GSCs differentiate, Stwl accumulates at boundaries between silenced and active gene compartments. Stwl at these boundaries plays a pivotal role in transitioning germ cell genes into a silenced state and activating a group of oocyte genes and nucleoporins (Nups). The upregulation of these Nups during differentiation is crucial for NPC formation and further genome organization. Thus, cross-talk between genome architecture and NPCs is essential for successful cell fate transitions.

UNASSIGNED: The introduction of Highly Active Anti-Retroviral Therapy (HAART) has led to a dramatic decrease in Human Immune Deficiency Virus (HIV) related morbidity and mortality in the developed as well as developing world. Whilst HAART has been effective in reducing rapidly progressive retinopathies, there are other ocular manifestations of HIV which are yet to be determined, characterised and addressed. The aim of the study was to determine the effect of HAART on Accommodative-Convergence mechanism among HIV/AIDS patients in Northwestern, Nigeria.
UNASSIGNED: This was hospital-based cohort study carried out from April 2019 to November 2019. Participants that met the inclusion criteria were recruited and were separated into two groups A and B. Group A were those about to commence HAART referred to as HAART naive, while group B were subdivided into four groups; comprising of B1: those that had been on HAART for 0 - 2½ years, group B2: >2½ - 5 years, group B3: >5 - 7½ years, and group B4: >7½ - 10 years, termed as HAART experience. Information obtained from the patients included sex, age, marital status, Near Point of Convergence (NPC), Amplitude of Accommodation (AA), Presbyopic reading Addition (ADD), CD4+ T cell count, HAART regimen and duration on HAART therapy.
UNASSIGNED: There were 400 participants aged 25 - 55years with a mean age of 37.86 ± 7.5years. The participant\'s NPC mean was 6.4 ± 1.47cm with a range of 2 - 18cm. Most of the participants 336 (84.0%) had an abnormal Near Point of Convergence compared to 64 (16%) with normal NPC values. The mean AA was 4.18± 1.34DS, ranging from 0.75 to 10.0DS and about 273 (68.2%) of the participant\'s AA was within 3 to 5DS. The mean presbyopic addition was 1.39± 0.98 DS ranging from 1.00 to 3.50DS whilst majority of the participants, 305 (76.2%) had an abnormal Reading Addition.
UNASSIGNED: The study showed that the HIV/AIDS patients on HAART exhibit an abnormally low AA, receded NPC and High presbyopic reading addition as compared to age matched HAART naïve. There was a statistically significant association between AA and HAART (p = 0.002) and HAART duration (p = 0.00), but there was no association with their CD4+ T cell levels and HAART regimen (p = 0.12, p = 0.08). There was no statistically significant association between Abnormal reading addition and HAART (p= 0.46), CD4+4 T cell levels and HAART regimen (p=0.53 and p= 0.59), but there was a statistically significant association with HAART duration (p= 0.00).

Autophagy is a critical player in lumbar intervertebral disk degeneration (IDD), and autophagy activation has been suggested to prevent the apoptosis of nucleus pulposus cells (NPCs). Myricetin has anti-cancer, anti-inflammatory, and antioxidant potentials and can activate autophagy. Thus, this study focused on the roles and mechanisms of myricetin in IDD. A puncture-induced rat IDD model was established and intraperitoneally injected with 20-mg/kg/day myricetin. Histopathological changes of intervertebral disks (IVDs) were assessed by hematoxylin and eosin staining and Safranin O/Fast Green staining. The isolated NPCs from IVDs of healthy rats were stimulated with IL-1β to mimic IDD-like conditions. The roles of myricetin in cell apoptosis, extracellular matrix (ECM) degradation, autophagy repression, and the JAK2/STAT3 pathway activation were examined by cell counting kit-8, flow cytometry, western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence staining. Myricetin treatment attenuated the apoptosis and ECM degradation, and enhanced autophagy in the IL-1β-treated NPCs, whereas the myricetin-mediated protection was limited by autophagy inhibition. Mechanistically, myricetin activated autophagy through blocking the JAK2/STAT3 signaling. In vivo experiments revealed that intraperitoneal injection of myricetin activated NPC autophagy to relieve puncture injury in rats. Myricetin prevents IDD by attenuating NPC apoptosis and ECM degradation through blocking the JAK2/STAT3 pathway to enhance autophagy.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.

In eukaryotic cells, the nuclear envelope (NE) is a membrane partition between the nucleus and the cytoplasm to compartmentalize nuclear contents. It plays an important role in facilitating nuclear functions including transcription, DNA replication and repair. In mammalian cells, the NE breaks down and then reforms during cell division, and in interphase it is restored shortly after the NE rupture induced by mechanical force. In this way, the partitioning effect is regulated through dynamic processes throughout the cell cycle. A failure in rebuilding the NE structure triggers the mixing of nuclear and cytoplasmic contents, leading to catastrophic consequences for the nuclear functions. Whereas the precise details of molecular mechanisms for NE reformation during cell division and NE restoration in interphase are still being investigated, here, we mostly focus on mammalian cells to describe key aspects that have been identified and to discuss the crosstalk between them.

Niemann-Pick disease (NPD) is another type of metabolic disorder that is classified as lysosomal storage diseases (LSDs). The main cause of the disease is mutation in the SMPD1 (type A and B) or NPC1 or NPC2 (type C) genes, which lead to the accumulation of lipid substrates in the lysosomes of the liver, brain, spleen, lung, and bone marrow cells. This is followed by multiple cell damage, dysfunction of lysosomes, and finally dysfunction of body organs. So far, about 346, 575, and 30 mutations have been reported in SMPD1, NPC1, and NPC2 genes, respectively. Depending on the type of mutation and the clinical symptoms of the disease, the treatment will be different. The general aim of the current study is to review the clinical and molecular characteristics of patients with NPD and study various treatment methods for this disease with a focus on gene therapy approaches.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.