The Spectrum of Oral Pathology Specimens: a Retrospective Study of 442 Specimens and a Review of Literature

Background: Diseases of the oral cavity are heterogenous in etiology, pathogenesis, histogenesis and clinical outcome. Several epidemiologic studies exist in the literature with variable and conflicting results, based on small sized-samples and geographic factors. The aim of this study is to examine the frequency of oral diseases encountered in our experience from a tertiary hospital and to compare it with previous studies.Methods: The archives of pathology at Jordan University Hospital were retrospectively searched for specimens of oral cavity and related structures anatomic areas between 2013-2020. Fisher’s exact test was performed to examine the statistical difference between the pathologic diagnosis and clinical variables of age, gender and site of specimen. One-way ANOVA test was applied to analyzed the differences in the mean of age among different pathologic groups. P-value of less than 0.05 was considered significant.Results: A total of four-hundred forty-one cases were retrieved. There were 232 (52%) females and 210 (48%) males. The range of age was 3-87 years (mean 43), 46 (10%) of which were children younger than 16 years. Inflammatory and reactive diseases were the most common, constituting 147 (33%) of all specimens, followed by benign neoplasms: 139 (31%), cysts: 114 (26%) then malignant diseases: 42 (10%). Lichen planus was the most common inflammatory disease: 26/147 (18%) and prevailed in patients older than 40 years (P = 00039). Keratocyst predominated in children and adolescents more than in adults (P = 0.0015). Buccal mucosa represented the most frequent site for biopsy: 76 (17%), followed by tongue and maxillary bone: 70 (16%), each. Conclusion: Inflammatory and benign neoplasms are the most common lesions in oral diseases. Oral malignancy appears to show a low to intermediate frequency compared to previous reports. The study provides a general overview of the spectrum of oral pathology specimens and points to some novel epidemiologic findings that suggests further investigations.

Tumor Treating Fields Suppression of Ciliogenesis Enhances Temozolomide Toxicity

Tumor Treating Fields (TTFields) are low intensity, alternating intermediate frequency (200kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells, or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation, and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low and high grade patient glioma cell lines that TTFields ablated cilia within 24 hours. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliated/ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Moreover, the inhibitory effects of TTFields and TMZ on tumor cell recurrence correlated with the relative timing of TMZ exposure to TTFields and ARL13B+ cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest TTFields efficacy may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.

Polycystic ovary rat model exposure to 150 kHz intermediate frequency: hypothalamic-pituitary-ovarian axis at the receptor, cellular, tissue, and hormone levels

Introduction The hypothalamic-pituitary-ovarian (HPO) axis is the principal regulator of the reproductive system. The neurons in the arcuate nucleus of the hypothalamus signal the basophilic cells of the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which bind to the granulosa and theca cells of a follicle in the ovary to promote healthy follicular development. Disruption of this process at any time can lead to polycystic ovaries and, if left untreated, can lead to Polycystic Ovarian Syndrome (PCOS), one of the leading causes of infertility. A novel treatment option using 150 kHz Intermediate Frequency (IF) Electromagnetic Radiation (EMR) has been proposed to monitor the effect of this frequency during cystic development. Methods To prove this, an experiment was conducted to study the effect of whole-body exposure to 150 kHz EMR for 8 weeks at receptor, cellular, tissue and hormonal levels on the HPO axis of 25 young cyclic female rats. Results The results showed that 150 kHz EMR did not affect the histoarchitecture of neurons of arcuate nucleus of the hypothalamus of PCO-induced rats. It was also found that the number of basophilic cells of the pituitary gland was increased and the immunoreactivity of LH and FSH secretion increased. This EMR field also decreased the development of follicular cysts in the ovary and possibly increased the immunoreactivity of the LH and FSH receptors as well on the theca and granulosa cells of follicles in the ovary. Conclusion There are still many limitations to this study. If properly evaluated, the results of this experiment could help develop a new non-invasive treatment option for women with PCOS in the near future.

The invention relates to an intermediate frequency power supply fast start and digital phase locked loop control technology

Intermediate frequency induction heating is widely used because of its low energy consumption and high thermal efficiency, but the speed of traditional intermediate frequency power supply is slow and its frequency tracking accuracy is limited. In order to maintain the resonant state of the load during the working process of the induction heating power supply and realize the automatic frequency tracking control during the working process. The frequency tracking of the 40kW intermediate frequency power supply is researched, and a method of combining the resonant frequency automatic identification algorithm and the digital phase locked loop frequency tracking control method is proposed. MATLAB simulation and experiment show that the system based on this control method can save the time of searching the load resonance frequency in the initial stage of the power supply, improve the frequency tracking speed, accelerate the dynamic response speed of the system, avoid the failure of frequency lock, and play the role of fast and stable startup.

BPSK Modulation-Based Local Oscillator-Free IQ Demodulation for Millimeter Wave Imaging

The precision of local oscillator (LO) signal in in-phase and quadrature (IQ) demodulation strongly affects the imaging performance of millimeter wave (mmWave) radars. Therefore, to eliminate the requirement for high-precision LO, a simple yet effective digital IQ demodulation method has been proposed with the aid of a specified sampling scheme in order to eliminate the demand for LO. Based on the bandpass sampling theorem, the characteristic of the intermediate frequency signal of mmWave imaging indicates that the LO is unrequired if the sampling rate is twice of the frequency of the carrier of the intermediate signal. In this way, the in-phase signal would be directly and accurately obtained by performing the Binary-Phase-Shift-Keying (BPSK) modulation on the samples, based on which the IQ demodulation would be completed by using the Hilbert transform. The proposed method does not employ LO and thus simplifies the demodulation process and is suitable for implementation in a Field-Programmable Gate Array (FPGA) with fewer hardware resources. To verify the method, a three-dimensional mmWave radar imaging is carried out at the 30-34 GHz bandwidth, where the sampling and digital IQ demodulation are realized by an ADC (AD9250) and FPGA (XC7K325T), respectively. The results show a simplified transceiver with lower requirements and the prospect of the proposed method being applied in radar imaging and other related fields.

DDRE-13. PROSTAGLANDIN E RECEPTOR 3 (PTGER3) REGULATES RESISTANCE TO TUMOR TREATING FIELDS (TTFields) IN GLIOBLASTOMA CELLS

INTRODUCTION TTFields, a novel approved therapy for GBM, employ alternating intermediate-frequency electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. The addition of TTFields significantly improves survival. However, most patients eventually develop resistance to TTFields through an unknown mechanism. METHODS Multiple human GBM cell lines were treated with TTFields continuously using Inovitro, an in vitro TTFields system, until cells with relative resistance to killing by TTFields emerged. Temporal gene expression profiles were analyzed using NETZEN, an innovative deep-learning and gene network-based ranking computational algorithm, to identify resistance pathways, followed by experimental validation. RESULTS PTGER3, a Gαi-protein-coupled cell surface receptor, is the top ranked master regulator in the predicted resistance program, which is upregulated in GBM cells within 24 hrs of exposure to TTFields and further reinforced as resistance sets in. Forced expression of PTGER3 in sensitive GBM cells confers relative resistance to TTFields, while PTGER3 depletion in resistant cells re-sensitizes them to TTFields. Most importantly, pharmacological inhibition of PTGER3 using either aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors effectively prevent resistance from developing. Mechanistically, PTGER3 is rapidly translocated from the plasma membrane to the nucleus after TTFields exposure, where it interacts with ZNF488, a stemness transcription factor tightly linked to PTGER3 in our predicted network to initiate and maintain the resistance program. Indeed, TTFields resistance is associated with a transition to glioma stem cells (GSCs) as determined by increased neurosphere formation and orthotopic tumorigenesis in immunocompromised mice, and PTGER3 inhibition alone reverses the GSC transition leading to improved tumor control and survival. CONCLUSIONS PTGER3 is at the apex of a novel pathway that indispensably regulates TTFields resistance through a unique mechanism involving the physical nuclear translocation of this 7-transmembrane receptor. PTGER3 and its pathway are thus potential therapeutic targets to enhance therapeutic efficacy of TTFields.

IMMU-35. INDUCTION OF ANTI-TUMOR IMMUNITY BY TUMOR TREATING FIELDS (TTFIELDS) IN GLIOBLASTOMA

INTRODUCTION The novel approved GBM treatment TTFields employs alternating, intermediate-frequency (200kHz) electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. Emerging evidence indicates that TTFields may also induce inflammation; however, the mechanism and whether this can be harnessed as cancer immunotherapy remain unclear. METHODS Multiple GBM cell lines were treated with TTFields using Inovitro, an in vitro TTFields system and integrity of the nuclear envelope and content and activation of key DNA sensor inflammatory pathways analyzed by immunostaining, expression profiling, and protein assays. In a syngeneic orthotopic murine model, TTFields-treated GBM cells were used to provide an in-situ vaccination platform. For validation, we performed bulk and single-cell RNAseq of PBMCs from 12 newly diagnosed GBM patients treated with TTFields. RESULTS TTFields induce focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that recruit and intensely activate the 2 major DNA sensors – cGAS and AIM2, and their cognate inflammasomes, thereby releasing pro-inflammatory cytokines and type-1 interferons (T1IFNs) that promote development and maturation of DCs and cytotoxic T cells. In murine model, TTFields-treated GBM cells induce anti-tumor memory immunity both intratumorally and systemically, producing a cure rate of 40% and partial immunity in an additional 25% in a STING- and AIM2-dependent manner. In patients with newly diagnosed GBM patients, we sequenced a total of 193,760 PBMCs and detected robust post-TTFields activation of adaptive immunity via the T1IFN trajectory anchored by plasmacytoid DCs, which was strongly correlated with the TCRαβ clonal expansion index observed in 11 of 12 patients (Spearman coefficient r=-0.8, P=0.014). Importantly, we also defined a T cell-based gene signature predictive of TTFields effects on T cell activation and TCRαβ clonal expansion. CONCLUSION Collectively, these studies define a novel strategy using TTFields to improve immunotherapy in GBM and potentially other solid tumors.