Sex Dimorphism in Pain Threshold and Neuroinflammatory Response: The Protective Effect of Female Sexual Hormones on Behavior and Seizures in an Allergic Rhinitis Model.

Our previous research demonstrated that allergic rhinitis could impact behavior and seizure threshold in male mice. However, due to the complex hormonal cycles and hormonal influences on behavior in female mice, male mice are more commonly used for behavioral tests. In this study, we aimed to determine whether these findings were replicable in female mice and to explore the potential involvement of sexual hormones in regulating neuroinflammation in an allergic model. Our results indicate that pain threshold was decreased in female mice with allergic rhinitis and the levels of IL-23/IL-17A/IL-17R were increased in their Dorsal root ganglia. However, unlike males, female mice with AR did not display neuropsychological symptoms such as learning and memory deficits, depression, and anxiety-like behavior. This was along with decreased levels of DNA methyl transferase 1 (DNMT1) and inflammatory cytokines in their hippocampus. Ovariectomized mice were used to mitigate hormonal effects, and the results showed that they had behavioral changes and neuroinflammation in their hippocampus similar to male mice, as well as increased levels of DNMT1. These findings demonstrate sex differences in how allergic rhinitis affects behavior, pain sensitivity, and seizure thresholds. Furthermore, our data suggest that DNMT1 may be influenced by sexual hormones, which could play a role in modulating inflammation in allergic conditions.

Effect of composite radiopacity and margin location of the restoration on the diagnosis of secondary caries.

This research aimed to evaluate the effect of the radiopacity of a Bulk-Fill composite (X-TraFil, VOCO, Germany) and a Conventional composite (P60, 3M ESPE, USA) and assessment of the margin location in the enamel and dentin on the diagnosis of secondary caries. 76 intact premolars with MOD preparation were divided into two equal groups and filled with the conventional and bulk-fill composite. Four regions were considered to simulate carious lesions (two regions in enamel and two regions in dentin). In each group, half of the regions in the dentin and half in the enamel were randomly selected for secondary caries simulation and filled with a wax-plaster combination while the remaining regions stayed intact. Bitewing imaging was done using the PSP digital sensor. Five examiners reviewed the images, and lesions were recorded. Caries diagnosis indicators and paired-sample t-test were used for statistical analysis. The reproducibility and accuracy of the examiners' responses were evaluated using the kappa and agreement coefficient (α=0.05). The sensitivity, specificity, and accuracy of diagnosing secondary carious lesions in enamel were significantly better under conventional than bulk-fill composite. Similarly, the sensitivity and accuracy of diagnosing secondary caries in dentin were significantly higher under conventional composite than bulk-fill composite (p<0.05). No significant differences were found in the agreement and kappa coefficient between conventional and bulk-fill composites in the enamel and dentin (p>0.05). The diagnostic accuracy of carious lesions was higher under conventional composite than bulk-fill composite. However, the location of the secondary was ineffective in caries diagnosis.

Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells.

The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.

Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery.

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in "hard-to-penetrate" tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Effect of composite radiopacity and margin location of the restoration on the diagnosis of secondary caries

Abstract This research aimed to evaluate the effect of the radiopacity of a Bulk-Fill composite (X-TraFil, VOCO, Germany) and a Conventional composite (P60, 3M ESPE, USA) and assessment of the margin location in the enamel and dentin on the diagnosis of secondary caries. 76 intact premolars with MOD preparation were divided into two equal groups and filled with the conventional and bulk-fill composite. Four regions were considered to simulate carious lesions (two regions in enamel and two regions in dentin). In each group, half of the regions in the dentin and half in the enamel were randomly selected for secondary caries simulation and filled with a wax-plaster combination while the remaining regions stayed intact. Bitewing imaging was done using the PSP digital sensor. Five examiners reviewed the images, and lesions were recorded. Caries diagnosis indicators and paired-sample t-test were used for statistical analysis. The reproducibility and accuracy of the examiners' responses were evaluated using the kappa and agreement coefficient (α=0.05). The sensitivity, specificity, and accuracy of diagnosing secondary carious lesions in enamel were significantly better under conventional than bulk-fill composite. Similarly, the sensitivity and accuracy of diagnosing secondary caries in dentin were significantly higher under conventional composite than bulk-fill composite (p<0.05). No significant differences were found in the agreement and kappa coefficient between conventional and bulk-fill composites in the enamel and dentin (p>0.05). The diagnostic accuracy of carious lesions was higher under conventional composite than bulk-fill composite. However, the location of the secondary was ineffective in caries diagnosis.

Resumo Essa pesquisa teve como objetivo avaliar o efeito da radiopacidade de resina composta Bulk-Fill (X-TraFil, VOCO, Alemanha) e de resina composta convencional (P60, 3M ESPE, EUA) e a avaliação da localização da margem no esmalte e na dentina no diagnóstico de cárie secundária. 76 pré-molares intactos com preparo MOD foram divididos em dois grupos iguais e restaurados de acordo com o grupo experimental. Quatro regiões foram consideradas para simular lesões de cárie (duas regiões no esmalte e duas regiões na dentina). Em cada grupo, metade das regiões na dentina e metade no esmalte foram selecionadas aleatoriamente para a simulação de cárie secundária e preenchidas com uma combinação de cera e gesso, enquanto as regiões restantes permaneceram intactas. As imagens de bitewing foram feitas usando o sensor digital PSP. Cinco examinadores analisaram as imagens, e as lesões foram registradas. Os indicadores de diagnóstico de cárie e o teste t de amostra pareada foram usados para análise estatística. A reprodutibilidade e a precisão das respostas dos examinadores foram avaliadas usando o kappa e o coeficiente de concordância (α=0,05). A sensibilidade, a especificidade e a precisão do diagnóstico de lesões cariosas secundárias no esmalte foram significativamente melhores com a resina composta convencional do que com a resina composta bulk-fill. Da mesma forma, a sensibilidade e a precisão do diagnóstico de cáries secundárias na dentina foram significativamente maiores com a resina convencional do que com a resina bulk-fill (p<0,05). Não foram encontradas diferenças significativas na concordância e no coeficiente kappa entre as resinas convencionais e bulk-fill no esmalte e na dentina (p>0,05). A precisão do diagnóstico de lesões cariosas foi maior com a resina composta convencional do que com a resina composta bulk-fill. Entretanto, a localização do secundário foi ineficaz no diagnóstico de cárie.

Effect of Toothpaste Fluoride Concentration on Color Stability of Resin Composites: An In Vitro Study

ABSTRACT Objective: To investigate the effects of two different dentifrice fluoride concentrations on the color stability of the composite. Material and Methods: Twenty-seven specimens (2×4×5 mm) each of microfilled (Gradia, GC, Japan) and nanohybrid (Grandio, VOCO, Germany) composites were prepared. The specimens were randomly divided into six groups (control, Fluoflor caries protection toothpaste with 1450ppm Fluoride (EXW, France), and Fluoflor kids toothpaste with 500ppm Fluoride (EXW, France) (n = 9). The specimens were immersed in a mixture of artificial saliva and toothpaste in a ratio of 1:3 and applied for 60 seconds every 12 hours for 42 days. The control samples were incubated in artificial saliva at 37°C. Primary and secondary color measurements were performed using color parameters (L∗a∗b) with a spectrophotoshade (MHT Optic Research AG, Niederhasli, Switzerland). Data were analyzed using a two-way analysis of variance at a significance level of 0.05. Results: According to the two-way ANOVA analysis, there was no significant difference in color change between the composites and no difference in the level of discoloration between different fluoride concentrations(p>0.05). Also, None of the dentifrices caused clinically significant color changes(∆E˂3.3). Conclusion: No clinically unacceptable color changes were observed in the microfilled and nanofilled composites with different concentrations of fluoride toothpaste.

Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate-glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83-13.94] and HR: 2.44, [CI 95%: 1.10-5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy.

Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice.

Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.

Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1α.

Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex-I inhibitors. The treatment downregulated genes mediating hypoxia-inducible factor (HIF)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1α (HIF-1α) signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

Slip-Coupled Electroosmosis and Electrophoresis Dictate DNA Translocation Speed in Solid-State Nanopores.

Controlling the DNA translocation speed is critical in nanopore sequencing, but remains rather challenging in practice, as attributable to a complex coupling between nanoscale fluidics and electrically mediated migration of DNA in a dynamically evolving manner. One important factor influencing the translocation speed is the DNA-liquid slippage stemming from the hydrophobic nature of the oligonucleotide, an aspect that has been widely ignored in the reported literature. In an effort to circumvent this conceptual deficit, here we first develop an analytical model to bring out the slip-mediated coupling between the electroosmosis and DNA-electrophoresis in a solid-state nanopore at low surface charge limits, ignoring the end effects. Subsequently, we compare these results with the numerical simulation data on electrokinetically modulated DNA translocation in such a nanopore, albeit of finite length with due accommodation of the end effects, connecting two end reservoirs by deploying a fully coupled Poisson-Nernst-Plank-Stokes flow model. Both the numerical and analytical results indicate that the DNA translocation speed is a linearly increasing function of the slip length, with more than four-fold increase being observed for a slip length as minimal as 0.5 nm as compared to the no-slip scenario. Considering specific strategies on demand for arresting high translocation speeds for accurate DNA sequencing, the above results establish a theoretical proposition for the same, premised on an analytical expression of the DNA-hydrophobicity modulated enhancement in the translocation speed for designing a nanopore-based sequencing platform─a paradigm that remained to be underemphasized thus far.

Effect of Laser and Conventional Office Bleaching and Polishing on the Color Change of Stained Nanohybrid and Microhybrid Composite Resin.

Aim: The present study investigated the effects of laser and conventional in-office bleaching, and polishing on the color of stained composite resin. Materials and Methods: A microhybrid composite (Clearfil AP-X) and a nanohybrid composite (Grandio) were selected. Twenty-four discs (2 × 10 mm) for each composite were prepared. The samples were immersed in coffee solution (25 g of coffee in 250 mL water) for seven days. Then the samples were divided into three groups (n = 8) and the stains were removed using bleaching (with Opalescence Xtra Boost), diode laser irradiation with Heydent material and a Sof-Lex polishing kit. The L ∗a ∗b ∗ color parameters were determined using a spectrophotometer before and after immersion and after stain removal procedures, and the overall color changes (ΔE) were calculated. The data were analyzed with two-way analysis of variance. Results: In the Clearfil composite resin group, the mean ΔE compared to the baseline using in-office bleaching, laser irradiation, and Sof-Lex polishing kit were 3.31, 3.35, and 4.93, respectively. These values with the Grandio composite resin were 3.31, 6.35, and 4.57, respectively. The highest capacity to remove stains was related to the conventional in-office bleaching method. Grandio composite resin underwent more color changes than Clearfil composite resin significantly (P-value < 0.05). Conclusion: Both composite resins exhibited color changes after immersion in the discoloring solution. However, after staining-removing procedures, the ΔE values decreased. Decreases in the ΔE values were not sufficient to restore the color to that before immersion in the discoloring solution with any stain-removing methods.

Ten-year follow-up report and neurologic sequelae in a case of neonatal severe primary hyperparathyroidism.

We present a 10-year follow-up and describe our experience in managing a case of neonatal severe primary hyperparathyroidism (NSHPT) for the first time in Iran. Microcephaly, mental retardation, and epilepsy may be long time sequels of NSHPT. The brain MRI findings are compatible with an old hypoxic-ischemic event.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Evaluation of diagnostic accuracy of CBCT and intraoral radiography for proximal caries detection in the presence of different dental restoration materials.

PURPOSE: This study aimed to assess the diagnostic accuracy of cone-beam computed tomography (CBCT) and digital intraoral radiography for the detection of proximal caries adjacent to amalgam, e.max porcelain, and metal-ceramic restorations (MCRs). MATERIALS AND METHODS: Parallel intraoral radiographs were obtained from 40 posterior teeth using PSP sensors. To obtain CBCT scans, the teeth were first radiographed alone, and were then positioned next to a tooth with an amalgam restoration, MCR, and e.max porcelain crown, and radiographed again. Two blinded observers scored radiographs using a four-point scale (0: absence of proximal caries, 1: enamel caries, 2: carious lesion extending to the outer half of dentin, 3: carious lesion extending to the inner half of dentin). Tooth sections were made, and the grade of caries was determined under a light microscope at x12 magnification. The sensitivity, specificity, and accuracy of CBCT and intraoral radiographs were then calculated. RESULTS: Artifact-free CBCT scans and intraoral radiographs had the highest diagnostic accuracy (0.826 and 0.657, respectively) while CBCT images of the teeth next to the amalgam restorations (0.526) had the lowest accuracy. The diagnostic accuracy of CBCT images of the teeth next to the porcelain crowns and MCRs was 0.613 and 0.601, respectively. CONCLUSION: Artifact-free CBCT images had higher diagnostic accuracy than intraoral radiography for the detection of all grades of proximal caries. The diagnostic accuracy of CBCT images of teeth adjacent to amalgam, porcelain, and MCRs was lower compared to intraoral radiographs and artifact-free CBCT images.

The current state of knowledge on how to improve skin flap survival: A review.

The incorporation of skin flaps in wound closure management with its cosmetic implications has appeared as a gleam of hope in providing desirable outcomes. Given the influence of extrinsic and intrinsic factors, skin flaps are prone to several complications, including ischemia-reperfusion injury (IRI). Numerous attempts have been undertaken to enhance the survival rate of skin flaps entailing pre/post-conditioning with surgical and pharmacological modalities. Various cellular and molecular mechanisms are employed in these approaches in order to reduce inflammation, promote angiogenesis and blood perfusion, and induce apoptosis and autophagy. With the emerging role of multiple stem cell lineages and their ability to improve skin flap viability, these approaches are increasingly being used to develop even more translationally applicable methods. Therefore, this review aims at providing current evidence around pharmacological interventions for improving skin flap survival and discussing their underlying mechanism of action.

The mTOR Signaling Pathway Interacts with the ER Stress Response and the Unfolded Protein Response in Cancer.

The mTOR complex 1 (mTORC1) coordinates several important environmental and intracellular cues to control a variety of biological processes, such as cell growth, survival, autophagy, and metabolism, in response to energy levels, growth signals, and nutrients. The endoplasmic reticulum (ER) is a crucial intracellular organelle that is essential for numerous cellular functions, including the synthesis, folding, and modification of newly synthesized proteins, stress responsiveness, and maintainence of cellular homeostasis. mTOR-mediated upregulation of protein synthesis induces the accumulation of misfolded or unfolded proteins in the ER lumen, which induces ER stress, leading to activation of the unfolded protein response (UPR) pathway. Reciprocally, ER stress regulates the PI3K/AKT/mTOR signaling pathway. Therefore, under pathologic conditions, the cross-talk between the mTOR and UPR signaling pathways during cellular stress can critically affect cancer cell fate and may be involved in the pathogenesis and therapeutic outcome of cancer. Here, we discuss accumulating evidence showing the mechanism of action, interconnections, and molecular links between mTOR signaling and ER stress in tumorigenesis and highlights potential therapeutic implications for numerous cancers.

The effect of dentin surface pretreatment using dimethyl sulfoxide on the bond strength of a universal bonding agent to dentin.

BACKGROUND: This study aimed to evaluate the effect of dentin pretreatment by Dimethyl Sulfoxide (DMSO) on the bond strength and microleakage of a universal bonding agent to dentin. METHODS: Fifty-six dentinal discs (thickness = 2 mm) were obtained from the crowns of the human third molars. The disks were assigned into 4 groups and treated as follows; self-etch-control group: G-Premio universal adhesive was used in self-etch mode, total-etch-control: G-Premio universal adhesive was used in total-etch mode, self-etch-DMSO: Water-based DMSO (50% volume) was applied on the samples for 60 s followed by application of G-Premio universal adhesive in self-etch mode, and Total-etch-DMSO: The samples were etched, and then, water-based DMSO was applied on them for 60 s followed by the application of G-Premio universal adhesive in total-etch mode. Afterward, resin composite was placed on all samples and light-cured. The samples were kept in distilled water and subjected to 5000 thermal cycles. Microshear bond strength was measured using the universal testing machine and failure modes were analyzed using a stereomicroscope. Forty-eight human third molars were used for microleakage evaluation and a standardized class five cavity was prepared on the buccal surface of each tooth. The teeth were assigned into 4 groups and received aforementioned surface treatment and the cavities were filled with resin composite. After storing in water for 24 h, the samples were subjected to 5000 cycles of thermocycling and the microleakage level of the samples was evaluated using silver nitrate uptake at the bonded interface. Two-way ANOVA test was used to analyze the effect of bonding technique (self-etch/ total-etch) and DMSO pretreatment on the microshear bond strength and microleakage of G-Premio adhesive to dentin. RESULTS: Bonding technique had no effect on the bond strength values (p = 0.17) while DMSO pretreatment significantly decreased the microshear bond strength of the samples (p = 0.001). DMSO application increased microleakage significantly in total-etch (P-value = 0.02) while it had no effect in self-etch mode (P-value = 0.44). CONCLUSIONS: Pretreatment of dentin using 50% DMSO significantly reduced the bond strength of G-Premio Bond in both self-etch and total-etch modes. DMSO effect on microleakage depended on the etching technique; DMSO increased the microleakage level when the adhesive was used in total-etch mode while did not affect the microleakage in self-etch mode.

Effect of charcoal-based dentifrices on surface roughness of an aged resin composite.

BACKGROUND: Recently, the use of whitening dentifrice has increased among patients. However, these products might increase the surface roughness of composite restorations and make them more susceptible to discoloration and plaque accumulation. This study aimed to compare the effects of two charcoal-based dentifrices and other whitening dentifrices with different mechanisms of action on the surface roughness of an aged resin composite. METHODS: Forty-five composite specimens were made (2 × 7mm) and their initial surface roughness was obtained using a Profilometer. The specimens were subjected to the Accelerated Artificial Aging (AAA) process for 300 hours. Then, the surface roughness of the specimens was reevaluated using the Profilometer. The specimens were randomly divided into 5 groups (N.=9), namely Control (Gc), Bencer (Gb; Sormeh Company, Tehran, Iran), Perfect White Black (Gp), Colgate Total Whitening (Gt), and Colgate Optic White (Go) (Colgate-Palmolive Company, New York, NY, USA). The specimens were brushed for 14 minutes with respective dentifrices. In the Gc group, the specimens were only brushed with distilled water. The surface roughness of the specimens was measured again. The data were analyzed using repeated measure ANOVA at a significance level of 0.05. RESULTS: There was no significant difference in surface roughness parameters (Ra, Rq, Rz) between the groups, but in each group, the roughness parameters decreased after the aging procedure and increased after brushing significantly except for Rz parameter in Gb group which increased after aging and decreased after brushing. CONCLUSIONS: None of the whitening dentifrices used in the present study had an adverse effect on the surface roughness of an aged composite resin.