Hyposalivation in patients with psoriasis: Association with severity, inflammatory, and anti-inflammatory cytokine biomarkers of the disease.

The aim of the study is to expound the effect of psoriasis on salivary glands by evaluating the secretion of saliva and salivary cytokine biomarkers in patients with psoriasis. This study was conducted by recruiting 120 subjects that included 60 patients diagnosed clinically with active psoriasis and 60 healthy controls who were age and gender matched to psoriatic subjects. Unstimulated whole saliva was collected from all the subjects by spitting method, and levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-2 (IL-2), and IL-10 (IL-10) were determined via enzyme-linked immunosorbent assay (BT Lab, Shanghai, China). Secretion of saliva in psoriasis patients was considerably reduced than in healthy controls. The concentrations of pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-2) were significantly increased, whereas level of anti-inflammatory cytokine (IL-10) was markedly decreased in the saliva of psoriasis patients with hyposalivation compared to healthy subjects. Our results demonstrated significant negative correlation of salivary flow rates with the disease severity. No significant correlations were obtained between salivary levels of tested cytokines and salivary flow rates in our study. Findings of the study reflect inflammation of salivary glands with reduced salivary flow rates in psoriasis patients. The inflammatory responses in salivary gland tissues by virtue of increased pro-inflammatory cytokines concentrations together with lower anti-inflammatory cytokine levels may have a role in affecting the saliva secretion in psoriasis patients. Secretion of unstimulated saliva in psoriasis patients decreases with the severity and duration of the disease.

Environment Friendly Rehydrants for Air-Dried Oral Buccal Smears - A Comparative Study with Conventional Method.

Background: Cytopathology is defined as a branch of pathology which involves studying diseases and their diagnosis. The conventional method involves fixing the cells in alcohol, but its poor availability in ill-equipped areas can pose problems. One solution to this problem is air-drying of smears followed by rehydration. In this study, we intend to assess the cytomorphologic changes in air-dried smears rehydrated using various agents and to correlate them with the smears prepared using conventional wet technique. Also, we attempt to find the alternative to alcohol which can be used in less equipped areas. Materials and Methods: Three smears each were prepared from 24 patients (12 healthy and 12 with habits). A total of 72 smears were prepared. One smear from each patient was used as control group (alcohol fixation - total number: 24 smears). The remaining two smears were air-dried and rehydrated and were taken as the test group (test group A - rehydrated with aq. glycerine; total number: 24 smears, test group B - rehydrated with coconut oil; total number: 24 smears) for 5-10 minutes. Then, all 72 slides were stained by standard Papanicolaou stain. The slides were examined for cytomorphologic changes and a score was assigned from 0 to 3. Conclusion: Our study proved aq. glycerine to be a superior rehydrant in comparison to conventional wet fixed smears or coconut oil. Also, in studies where cytoplasmic evaluation is required, coconut oil can be used due to its superior quality.

Enhanced therapeutic action of Trastuzumab loaded ZnxMn1-xFe2O4 nanoparticles using a pre-treatment step for hyperthermia treatment of HER2+ breast cancer.

In this study, Ferrites (Fe3O4, MnFe2O4, ZnFe2O4) and different stoichiometric ratios of ZnxMn1-xFe2O4 (x = 0.2, 0.4, 0.6, and 0.8) nanoparticles (<15 nm) were synthesized by microwave-assisted method and optimised for hyperthermia studies. The selection of the optimised variant of ferrite i.e. Zn0.4Mn0.6Fe2O4 was found to be the best variant based on VSM (38.14 emu g-1) hyperthermia-based temperature rise (maximum ΔT of 38 °C), SAR and ILP values. Trastuzumab, which is known to bind with HER2 receptors of breast cancer was chemically tethered onto Zn0.4Mn0.6Fe2O4 nanoparticles through EDC/NHS coupling with a loading efficiency of 80%. The attached Trastuzumab aided during the pre-treatment step by aiding in the internalisation of Zn0.4Mn0.6Fe2O4 nanoparticles, with cellular uptake of 11% in SK-BR-3 (cancerous HER2+) cells compared to ∼5% for MDA-MB-231 (cancerous HER2-) and RPE-1 (non-cancerous) cells. In the presence of a hyperthermia trigger for 15 mins, ZnxMn1-xFe2O4 -Trastuzumab formulation had a maximum therapeutic effect by reducing the SK-BR-3 cell viability to 14% without adversely affecting the RPE-1 cells. The mechanism of ZnxMn1-xFe2O4-Trastuzumab combination was examined using an internalisation study, MTT-based viability, proliferation study, and ROS generation assay. By utilizing both Trastuzumab and hyperthermia, we achieve their synergistic anticancer properties while minimizing the drug requirement and reducing any effect on non-cancerous cells.

Purine Synthesis Inhibitor L-Alanosine Impairs Mitochondrial Function and Stemness of Brain Tumor Initiating Cells.

Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in purine salvage, we demonstrate that purine blockade via treatment with L-Alanosine (ALA), an inhibitor of de novo purine synthesis, attenuates stemness of MTAP-deficient GBM cells. This ALA-induced reduction in stemness is mediated in part by compromised mitochondrial function, highlighted by ALA-induced elimination of mitochondrial spare respiratory capacity. Notably, these effects of ALA are apparent even when the treatment was transient and with a low dose. Finally, in agreement with diminished stemness and compromised mitochondrial function, we show that ALA sensitizes GBM cells to temozolomide (TMZ) in vitro and in an orthotopic GBM model. Collectively, these results identify purine supply as an essential component in maintaining mitochondrial function in GBM cells and highlight a critical role of mitochondrial function in sustaining GBM stemness. We propose that purine synthesis inhibition can be beneficial in combination with the standard of care for MTAP-deficient GBMs, and that it may be feasible to achieve this benefit without inflicting major toxicity.

ACR Appropriateness Criteria® Low Back Pain: 2021 Update.

In the United States, acute low back pain, with or without radiculopathy, is the leading cause of years lived with disability and the third ranking cause of disability-adjusted life-years. Uncomplicated acute low back pain and/or radiculopathy is a benign, self-limited condition that does not warrant any imaging studies. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags, raising suspicion for a serious underlying condition, such as cauda equina syndrome, malignancy, fracture, or infection. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Plexopathy: 2021 Update.

Plexopathy may be caused by diverse pathologies, including trauma, nerve entrapment, neoplasm, inflammation, infection, autoimmune disease, hereditary disease, and idiopathic etiologies. For patients presenting with brachial or lumbosacral plexopathy, dedicated plexus MRI is the most appropriate initial imaging modality for all clinical scenarios and can identify processes both intrinsic and extrinsic to the nerves. Other imaging tests may be appropriate for initial imaging depending on the clinical scenario. This document addresses initial imaging strategies for brachial and lumbosacral plexopathy in the following clinical situations: nontraumatic plexopathy with no known malignancy, traumatic plexopathy (not perinatal), and plexopathy occurring in the context of a known malignancy or posttreatment syndrome. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Suspected Spine Infection.

Spine infection is both a clinical and diagnostic imaging challenge due to its relatively indolent and nonspecific clinical presentation. The diagnosis of spine infection is based upon a combination of clinical suspicion, imaging evaluation and, when possible, microbiologic confirmation performed from blood cultures or image-guided percutaneous or open spine biopsy. With respect to the imaging evaluation of suspected spine infection, MRI without and with contrast of the affected spine segment is the initial diagnostic test of choice. As noncontrast MRI of the spine is often used in the evaluation of back or neck pain not responding to conservative medical management, it may show findings that are suggestive of infection, hence this procedure may also be considered in the evaluation of suspected spine infection. Nuclear medicine studies, including skeletal scintigraphy, gallium scan, and FDG-PET/CT, may be helpful in equivocal or select cases. Similarly, radiography and CT may be appropriate for assessing overall spinal stability, spine alignment, osseous integrity and, when present, the status of spine instrumentation or spine implants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization.

Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase (MTAP), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents. IMPLICATIONS: PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents.

Intestinal Perforation: A Rare Complication of Treatment With Bevacizumab.

Bevacizumab, a monoclonal immunoglobulin-G1 antibody directed against vascular endothelial growth factor (VEGF), inhibits angiogenesis. Gastrointestinal perforation is a serious and often fatal adverse event related to bevacizumab use. Bevacizumab is indicated in the treatment of colorectal malignancies, certain subtypes of non-small cell lung carcinoma, metastatic renal cell carcinomas, and cervical cancers. It is also indicated in the treatment of recurrent glioblastoma (GBM) in adult patients as the sole treatment agent or in combination with other antineoplastic medications. We present a case of a patient on bevacizumab currently with glioblastoma multiforme and seizures, who was previously treated with radiation treatment and temozolomide. The patient presented to the emergency room with abdominal pain, seizures and was diagnosed to have an intestinal perforation.

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells.

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of PROM1/CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of PROM1/CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in MTAP-null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133+ cells in MTAP-null GBM can be effectively depleted by inhibition of de novo purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.

Dentinogenic ghost-cell tumor of the maxilla: A case report and review of literature.

Dentinogenic ghost-cell tumor (DGCT) is a rare, odontogenic neoplasm which is considered to be a solid variant of the calcifying odontogenic cyst (COC) with locally aggressive behavior and is characterized by ameloblastoma-like epithelial islands, ghost cells and dentinoid. It accounts for only 2%-14% of all COCs. Herewith, we report the case of DGCT in a 40-year-old male patient with clinical presentation as swelling on the right side of the face.

The reduced activity of PP-1α under redox stress condition is a consequence of GSH-mediated transient disulfide formation.

Heart failure is the most common cause of morbidity and hospitalization in the western civilization. Protein phosphatases play a key role in the basal cardiac contractility and in the responses to ß-adrenergic stimulation with type-1 phosphatase (PP-1) being major contributor. We propose here that formation of transient disulfide bridges in PP-1α might play a leading role in oxidative stress response. First, we established an optimized workflow, the so-called "cross-over-read" search method, for the identification of disulfide-linked species using permutated databases. By applying this method, we demonstrate the formation of unexpected transient disulfides in PP-1α to shelter against over-oxidation. This protection mechanism strongly depends on the fast response in the presence of reduced glutathione. Our work points out that the dimerization of PP-1α involving Cys39 and Cys127 is presumably important for the protection of PP-1α active surface in the absence of a substrate. We finally give insight into the electron transport from the PP-1α catalytic core to the surface. Our data suggest that the formation of transient disulfides might be a general mechanism of proteins to escape from irreversible cysteine oxidation and to prevent their complete inactivation.

Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren's Syndrome patients.

Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer.

During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc- antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.

Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis.

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events.

Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.

Mandibular plasmacytoma of jaw - a case report.

The plasma cell neoplasm may present as Extramedullary Plasmacytoma (EMP) in soft tissues in bone as a Solitary Plasmacytoma of bone (SPB) or as a part of multi focal disseminated disease Multiple Myeloma (MM). The majority of 80% occurs in head and neck region. In our case, a 62-year-old male patient presented with a non tender swelling of short duration. The swelling was noted obliterating the vestibular depth in right lower mandibular region. The radiological features were non specific.

Alterations in serum lipid profile patterns in oral cancer: correlation with histological grading and tobacco abuse.

Albeit alterations in serum lipid profile patterns have long been associated with malignancies, still role of these alterations remains controversial. It has been suggested a causative relationship might exist between plasma lipid levels and oral cancer patients. Further, the habit of tobacco consumption is on the rise and most often the oral cancer patients are afflicted with this menace. As a matter of fact, tobacco contains carcinogens capable of damaging the cell membrane components including lipids. Thus, the purpose of the present review is to discuss the basics of lipids and to evaluate alterations in plasma lipid profile in oral cancer patients and its association with histological grading and tobacco abuse. Pertinent literature was searched in PubMed and Medline by using key words such as serum lipid profile, oral cancer, histological grades and tobacco abuse.

Arteriovenous malformation of the oral cavity.

Vascular anomalies are a heterogeneous group of congenital blood vessel disorders more typically referred to as birthmarks. Subcategorized into vascular tumors and malformations, each anomaly is characterized by specific morphology, pathophysiology, clinical behavior, and management approach. Hemangiomas are the most common vascular tumors. Lymphatic, capillary, venous, and arteriovenous malformations make up the majority of vascular malformations. Arteriovenous malformation of the head and neck is a rare vascular anomaly but when present is persistent and progressive in nature and can represent a lethal benign disease. Here we present a case report of a 25-year-old male patient with arteriovenous malformation involving the base of tongue.