Unusual localized gingival redness: a case report.

Inflammation of the gingiva is one of the most common and routine findings in dental practice. These routine appearances of inflammatory gingivae can show peculiarity when associated with an underlying systemic condition or because of reactive, benign, or malignant pathologies. This case highlights minute clinical signs of the gingiva that deviate from the routine presentation and warrant further investigations. A 63-year-old woman presented with a chief complaint of severe pain in relation to the lower front teeth region for 1 month. Intraoral examination revealed a gingival lesion on the labial aspect of 41, 42, and 43, and an intraoral periapical radiograph showed mild bone loss. The lesion persisted despite oral prophylaxis, and a biopsy was advised. The final diagnosis was stage 1 gingival squamous cell carcinoma (GSCC). It is important to note that the non-descript presentation of GSCC in early stages often mimics benign traumatic or inflammatory lesions of the gingiva. Peculiar clinical features of GSCC of note include the lack of traditionally associated risk factors and localized red or ulcerative lesions with increased bleeding tendencies that do not respond to routine periodontal treatment within 2 weeks.

The Effects of NLY01, a Novel Glucagon-Like Peptide-1 Receptor Agonist, on Cuprizone-Induced Demyelination and Remyelination: Challenges and Future Perspectives.

Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2+PDGFRa-) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2+CC1+ cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.

Multiple sclerosis and Moyamoya angiopathy: Mimic and misdiagnosis.

Moyamoya Angiopathy (MMA) is frequently not considered in differential diagnosis of Multiple Sclerosis (MS). This is the first study to prospectively analyze rate of misdiagnosis of MMA as MS and its clinical implications. Of the 160 angiographically proven MMA, 5 patients had an initial misdiagnosis of MS (3.13%). These 5 cases had female-predominance (80%).Out of the 5 cases, 4 cases (80%) presented with hemiparesis; 3 cases (60%) had an immediate precipitating factor. Radiologically, presence of both periventricular and juxtacortical white-matter-lesions was seen in 4 out of 5 cases (80%);none had infratentorial/spinal lesion, while all 5 cases had presence of "Ivy" sign and abnormal flow voids. Differentiation relies on careful evaluation of clinico-radiological features. MMA should be considered as a rare but important differential to MS.

The Role of Circulating Protein and Metabolite Biomarkers in the Development of Pancreatic Ductal Adenocarcinoma (PDAC): A Systematic Review and Meta-analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and this is attributed to it being diagnosed at an advanced stage. Understanding the pathways involved in initial development may improve early detection strategies. This systematic review assessed the association between circulating protein and metabolite biomarkers and PDAC development. METHODS: A literature search until August 2020 in MEDLINE, EMBASE, and Web of Science was performed. Studies were included if they assessed circulating blood, urine, or salivary biomarkers and their association with PDAC risk. Quality was assessed using the Newcastle-Ottawa scale for cohort studies. Random-effects meta-analyses were used to calculate pooled relative risk. RESULTS: A total of 65 studies were included. Higher levels of glucose were found to be positively associated with risk of developing PDAC [n = 4 studies; pooled relative risk (RR): 1.61; 95% CI: 1.16-2.22]. Additionally, an inverse association was seen with pyridoxal 5'-phosphate (PLP) levels (n = 4 studies; RR: 0.62; 95% CI: 0.44-0.87). Meta-analyses showed no association between levels of C-peptide, members of the insulin growth factor signaling pathway, C-reactive protein, adiponectin, 25-hydroxyvitamin D, and folate/homocysteine and PDAC risk. Four individual studies also reported a suggestive positive association of branched-chain amino acids with PDAC risk, but due to differences in measures reported, a meta-analysis could not be performed. CONCLUSIONS: Our pooled analysis demonstrates that higher serum glucose levels and lower levels of PLP are associated with risk of PDAC. IMPACT: Glucose and PLP levels are associated with PDAC risk. More prospective studies are required to identify biomarkers for early detection.

Moyamoya disease: a spectrum of clinical and radiological findings in a series of eight paediatric patients.

Moyamoya disease (MMD) is a progressive steno-occlusive vasculopathy at the circle of Willis, characteristically involving the supra-clinoid segment of internal carotid arteries and their proximal branches with prominent collateral artery formation. Here we present, a series of imaging findings and varied clinical presentation of eight cases (n = 8) of MMD in the pediatric population (aged 0-18 years) after a retrospective review and detailed clinical evaluation. Detailed clinical history and examination were performed of eight pediatric patients of MMD with varied presentations. Magnetic resonance imaging (MRI) of the brain along with time of flight (TOF) sequence magnetic resonance angiography (MRA) was performed for all patients with a 3 T ((T) SEIMENS MRI scanner. Three out of eight cases (37.5%) presented with imaging findings of acute parenchymal infarction involving one or more major vascular territories showing diffusion restriction on DWI (diffusion-weighted image) sequence. Two of the patients (25%) showed chronic infarction with areas of gliosis and encephalomalacia. One child presented with watershed areas of infarction involving bilateral parieto-occipital region. In one of the patients (12.5%) being evaluated for dystonia, the only parenchymal finding detected was that of asymmetric ventriculomegaly. A solitary patient being evaluated for intermittent focal seizure followed by Todd's hemiparesis had normal parenchymal brain imaging. Leptomeningeal pattern of enhancement was noted in one patient (12.5%). Although predominantly an intracranial vasculopathy, MMD may have myriad presentations apart from stroke, some of which are highlighted in this series.

Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice.

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.

The Multiple Roles of the IAP Super-family in cancer.

The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes. IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor κB (NF-κB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.

Oral manifestations in chronic kidney disease patients undergoing hemodialysis: a hospital-based study.

BACKGROUND: Chronic kidney disease (CKD-HD) patients undergoing routine hemodialysis have been reported to have oral signs and symptoms due to disease process or various comorbidities like diabetes mellitus (DM). Both CKD and DM can cause oral changes. Hence this study aimed to evaluate the prevalence of oral symptoms and signs in CKD-HD patients and to rule out DM as possible confounding factor for the oral findings. METHODS: Oral manifestations were assessed in 102 CKD-HD patients, and compared with 100 DM patients and 101 non-diabetic patients with no renal impairment. RESULTS: Most common symptom reported by patients with CKD-HD were xerostomia, altered taste. The most prevalent objective findings were oral dryness. There was statistically significant difference in symptoms and signs between CKD-HD and non-CKD patients. However, no significant difference between CKD-HD with and without DM. CONCLUSIONS: This study showed increased prevalence of oral findings in CKD patients. It also revealed that Diabetes mellitus cannot be a contributing factor for increased prevalence of oral manifestations in CKD patients.

Comprehensive proteomics investigation of P. vivax-infected human plasma and parasite isolates.

BACKGROUND: In recent times, Plasmodium vivax (P. vivax) has become a serious threat to public health due to its ability to cause severe infection with fatal outcomes. Its unique biology makes it resilient to control measures that are otherwise effective against P. falciparum. A deeper understanding of P. vivax biology and pathogenesis is, therefore, essential for developing the right control strategies. Proteomics of P. falciparum has been helpful in studying disease biology and elucidating molecular mechanisms involved in the development of disease. However, unlike P. falciparum, proteomics data for P. vivax infection is minimal due to the absence of a continuous culture system. The dependence on clinical samples and animal models has drastically limited P. vivax research, creating critical knowledge gaps in our understanding of the disease. This study describes an in-depth proteomics analysis of P. vivax-infected human plasma and parasite isolates, to understand parasite biology, pathogenesis, and to identify new diagnostic targets for P. vivax malaria. METHODS: A mass-spectrometry- (MS) based proteomics approach (Q Exactive) was applied to analyze human plasma and parasite isolates from vivax malaria patients visiting a primary health centre in India. Additionally, a targeted proteomics assay was standardized for validating unique peptides of most recurring parasite proteins. RESULTS: Thirty-eight P. vivax proteins were detected in human plasma with high confidence. Several glycolytic enzymes were found along with hypothetical, cytoskeletal, ribosomal, and nuclear proteins. Additionally, 103 highly abundant P. vivax proteins were detected in parasite isolates. This represents the highest number of parasite proteins to be reported from clinical samples so far. Interestingly, five of these; three Plasmodium exported proteins (PVX_003545, PVX_003555 and PVX_121935), a hypothetical protein (PVX_083555) and Pvstp1 (subtelomeric transmembrane protein 1, PVX_094303) were found in both plasma and parasite isolates. CONCLUSIONS: A parasite proteomics investigation is essential to understand disease pathobiology and design novel interventions. Control strategies against P. vivax also depend on early diagnosis. This work provides deeper insights into the biology of P. vivax by identifying proteins expressed by the parasite during its complex life-cycle within the human host. The study also reports antigens that may be explored as diagnostic candidates.

Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling.

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient's benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.

Customized Cheek Plumper with Friction Lock Attachment for a Completely Edentulous Patient to Enhance Esthetics: A Clinical Report.

Prosthetic rehabilitation of a completely edentulous patient should never be restricted to the replacement of missing teeth. The ultimate aim of complete denture treatment should be restoration of the full range of oral functions and esthetics. Slumped cheeks are always a concern for esthetically demanding complete denture patients. This article describes a simple, scientific, cost-effective technique to improve facial esthetics in a completely edentulous patient with the help of a cheek plumper. The technique used here implements the concept of neutral zone to precisely determine the amount of space available for the cheek plumper. The simple friction lock attachments that retained the cheek plumpers on the prosthesis were also fabricated after determining the space available in the appropriate areas. Thus an effort was made to keep the cheek plumpers unobtrusive yet effective to ensure complete integration of the prosthesis into the stomatognathic system.

The Hollow Maxillary Complete Denture: A Simple, Precise, Single-Flask Technique Using a Caramel Spacer.

The success of removable prostheses ultimately depends on a number of factors such as retention, stability, support, esthetics, and masticatory function. Increased intraoral inter-arch distance leads to an increase in the weight of the prosthesis. This may compromise the retention and resistance, which are key for a successful removable prosthesis. Various methods, techniques, and materials have been reported to minimize the weight of a prosthesis. This article describes a simple, unique, precise single-flask technique for the fabrication of a lightweight maxillary prosthesis using caramel as a 3D spacer, which was "indexed" to obtain a uniform thickness of acrylic around the hollow cavity.

An Uncommon Meridional Globe Rupture due to Blunt Eye Trauma.

Open globe injury (OGI) is a severe form of eye trauma. It is an important cause of monocular blindness worldwide. Ruptures from blunt trauma are most common at the sites where the sclera is thinnest, at the insertions of the extraocular muscles, and at the limbus. Most often, rupture is equatorial. We present a unique case of open globe injury due to blunt ocular trauma from a thrown rock that resulted in a meridional rupture of the eye. The pertinent literature is reviewed.

Unexplored benefits of controlled ice nucleation: Lyophilization of a highly concentrated monoclonal antibody solution.

The study explores new benefits of controlled ice nucleation during lyophilization. A highly concentrated monoclonal antibody product was lyophilized using conventional (uncontrolled) and controlled ice nucleation freezing and the processes were compared for their impact on process performance, reconstitution time, and product quality attributes. Glass fogging was observed during the conventional ice nucleation freezing step and is investigated. A mechanical stress study was also conducted on the lyophilized product manufactured using uncontrolled and controlled ice nucleation to measure and compare propensity toward aggregation upon physical stresses associated with shipping and handling. Reduction in primary drying time and reconstitution time was achieved with controlled ice nucleation. In contrast to significant fogging observed for uncontrolled nucleation, glass fogging was absent in vials subjected to controlled ice nucleation. Uncontrolled nucleation freezing produced higher number of particles when subjected to mechanical stress prior to reconstitution compared to controlled nucleation lyophilized samples. The study confirms published benefits of controlled ice nucleation (e.g. reduction in primary drying time). The manuscript reports for the first time the advantage that controlled ice nucleation may offer in regards to glass fogging during lyophilization. The reduced number of particles in the controlled nucleated samples exposed to mechanical stress suggest that frictional forces play an important role in governing the stability of protein in the lyophilized state.

HIV-1 Activation of Innate Immunity Depends Strongly on the Intracellular Level of TREX1 and Sensing of Incomplete Reverse Transcription Products.

TREX1 has been reported to degrade cytosolic immune-stimulatory DNA, including viral DNA generated during HIV-1 infection; but the dynamic range of its capacity to suppress innate immune stimulation is unknown, and its full role in the viral life cycle remains unclear. A main purpose of our study was to determine how the intracellular level of TREX1 affects HIV-1 activation and avoidance of innate immunity. Using stable overexpression and CRISPR-mediated gene disruption, we engineered a range of TREX1 levels in human THP-1 monocytes. Increasing the level of TREX1 dramatically suppressed HIV-1 induction of interferon-stimulated genes (ISGs). Productive infection and integrated proviruses were equal or increased. Knocking out TREX1 impaired viral infectivity, increased early viral cDNA, and caused 10-fold or greater increases in HIV-1 ISG induction. Knockout of cyclic GMP-AMP synthase (cGAS) abrogated all ISG induction. Moreover, cGAS knockout produced no increase in single-cycle infection, establishing that HIV-1 DNA-triggered signaling is not rapid enough to impair the initial ISG-triggering infection cycle. Disruption of the HIV-1 capsid by PF74 also induced ISGs, and this was TREX1 level dependent, required reverse transcriptase catalysis, and was eliminated by cGAS gene knockout. Thus, the intracellular level of TREX1 pivotally modulates innate immune induction by HIV-1. Partial HIV-1 genomes are the TREX1 target and are sensed by cGAS. The nearly complete lack of innate immune induction despite equal or increased viral integration observed when the TREX1 protein level is experimentally elevated indicates that integration-competent genomes are shielded from cytosolic sensor-effectors during uncoating and transit to the nucleus.IMPORTANCE Much remains unknown about how TREX1 influences HIV-1 replication: whether it targets full-length viral DNA versus partial intermediates, how intracellular TREX1 protein levels correlate with ISG induction, and whether TREX1 digestion of cytoplasmic DNA and subsequent cGAS pathway activation affects both initial and subsequent cycles of infection. To answer these questions, we experimentally varied the intracellular level of TREX1 and showed that this strongly determines the innate immunogenicity of HIV-1. In addition, several lines of evidence, including time-of-addition experiments with drugs that impair reverse transcription or capsid integrity, showed that the pathogen-associated molecular patterns sensed after viral entry contain DNA, are TREX1 and cGAS substrates, and are derived from incomplete reverse transcriptase (RT) products. In contrast, the experiments demonstrate that full-length integration-competent viral DNA is immune to TREX1. Treatment approaches that reduce TREX1 levels or facilitate release of DNA intermediates may advantageously combine enhanced innate immunity with antiviral effects.

Clinical Proteomics and Cytokine Profiling for Dengue Fever Disease Severity Biomarkers.

Dengue fever (DF) is a major global health burden with a pathophysiology that is still incompletely understood. Biomarkers that predict and explain susceptibility to DF and its progression to its more severe hemorrhagic form are much needed. DF is endemic in tropical and subtropical regions of the world, with a rapidly increasing incidence of disease severity. We conducted a clinical biomarker discovery study using both a case-control and longitudinal study design. Plasma proteome alterations in patients with DF (n = 12) and dengue hemorrhagic fever (DHF, n = 24) were analyzed in comparison to healthy controls (HCs, n = 16), using the isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics methodology (false discovery rate of 1%, ≥2 peptides). Several proteins such as the alpha-2 macroglobulin, angiotensinogen, apolipoprotein B-100, serotransferrin, and ceruloplasmin were upregulated (fold change >1.2) in all DHF cases, and downregulated in DF (fold change <0.83), compared with HCs. Plasma cytokine profiling (8 DF, 8 DHF, and 8 HC) on two consecutive time points, at day 0 (day of admission) and days 5-7, found significant elevation in IL-1RA, IL-7, TNF-α, MCP1-MCAF, and MIP-1ß levels, but only in the DHF cases, which is the severe disease, and not in DF, compared with HCs (p < 0.05). These new observations on changes in the plasma proteome and cytokine profiles in patients with dengue infection identify several putative molecular leads for future biomarker development and precision medicine in relation to forecasting DF disease severity.

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells.

A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRß. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma.