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The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.

Supplementary Video from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

Supplementary Data from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities.Significance:How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun–dependent manner.See related commentary by Amit and Maitra, p. 2240.This article is highlighted in the In This Issue feature, p. 2221

Supplementary Figure from Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion

The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neural invasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neural-invasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associate with dorsal root ganglia than non-leading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion. Citation Format: Qi Wang, Andrea Marcadis, Elizabeth Kao, Chun-Hao Chen, Laxmi Gusain, Ann Powers, Richard Bakst, Sylvie Deborde, Richard J. Wong. Rapid cancer cell perineural invasion utilizes amoeboid migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB158.

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SCs) activated by cancer cells collectively function as Tumor Activated Schwann cell Tracks (TASTs) that promote cancer cell migration and invasion. Non-myelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities.SIGNIFICANCEHow the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that Schwann cells are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun dependent manner.

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities. Significance: How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun–dependent manner. See related commentary by Amit and Maitra, p. 2240. This article is highlighted in the In This Issue feature, p. 2221

Both oral health problems and depression among pregnant women contribute to maternal–infant health outcomes. Little is known, however, about the potential effects of clinically significant depression on the oral health status of pregnant women. The purpose of the present study was to determine the influence of clinically significant depression and rural- or urban-dwelling status on oral health outcomes among pregnant women. Pregnant women ( N = 685) in rural (i.e., West Virginia) and urban (i.e., Pittsburgh, PA) areas of northern Appalachia were assessed by calibrated examiners regarding gingivitis, oral hygiene, and DMFT (decayed, missing, and filled teeth), completed the Center for Epidemiologic Studies–Depression Scale (CES-D) and provided demographics. Participants were categorized based on clinically significant depressive symptoms (CES-D ≥ 16) and rural/urban domicile. Women with depression and those living in rural areas had worse oral health on all three indices than their non-depressed and urban counterparts. Depression, particularly among women in rural areas, affects certain oral health indices and represents a modifiable target for intervention. Moreover, treatments designed specifically for rural populations may be of particular utility. Women who are pregnant or planning to become pregnant may benefit from regular depression screenings from their dental and medical health care providers.

Background With the population of octogenarians projected to increase fourfold by 2050, we sought to compare outcomes of laparoscopic versus open approach in octogenarians requiring surgery for adhesive small bowel obstruction (SBO). Methods/Materials and methods Using 2006-2015 American College of Surgeons National Surgical Quality Improvement Project, we identified patients aged ≥80 y who underwent emergency surgery within 1 d of admission for SBO. Risk variables of interest included age, sex, race, body mass index, preoperative sepsis, and American Society of Anesthesiologists (ASA) classification. Outcomes included length of stay, mortality, and pneumonia. Univariable and multivariable analyses were performed. Results Eight hundred fifty-six patients were identified. Six hundred ninety-nine (81.7%) underwent laparotomy; 157 (18.3%) underwent laparoscopy. Twenty-four (15.3%) of laparoscopic cases were converted. There was no difference between the open and laparoscopic groups in age, and race, preoperative albumin, or preoperative sepsis. The open group had higher rates of totally dependent functional status, congestive heart failure, chronic obstructive pulmonary disease, and higher ASA class. There was no difference in operative time. Laparoscopy was associated with shorter length of stay. The open approach showed higher rates of postoperative pneumonia, myocardial infarct, and mortality. Multivariable analysis showed increased age, functional status, preoperative albumin, and ASA class associated with mortality. The operative approach was not associated with mortality. Postoperative pneumonia was associated with male sex and open approach. Conclusions Age, preoperative functional status, low preoperative albumin, and ASA classes IV and V were associated with mortality, while the open approach and male sex were associated with postoperative pneumonia. Octogenarians who present with SBO due to adhesive disease may benefit from an initial laparoscopic exploration. Further prospective studies are warranted.

Hormonal changes have been implicated in the phenomenon of pain modulation during pregnancy. The role of psychosocial constructs such as fear and anxiety related to pain during pregnancy, however, has largely been overlooked. The current study investigated the cross-sectional associations between the report of pain-related fear among pregnant and non-pregnant female participants. The study consisted of three different convenience samples: pregnant females (N=1171; age: M=28.61, SD=5.3), non-pregnant female undergraduate students (N=274; age M=19.81, SD=3.9), and non-pregnant female patients (N=212) diagnosed with chronic pain (Age: M=46.06, SD=12.7). Participants completed the Fear of Pain Questionnaire-9 in order to determine their fear related to severe, minor, medical/dental, and overall fear of pain. There were significant differences among the three groups in their overall fear of pain (F(2,1649)=25.38, p

The recruitment of community-dwelling older adults, particularly those with cognitive impairment and those residing in rural areas, has been consistently challenging for researchers, especially in the dental field. This study reports on recruitment experiences from an ongoing study investigating the association between oral health and cognitive status in later life. Multiple recruitment strategies, including educational presentations and traveling to participants’ homes, were used to enroll rural elderly participants with various levels of cognitive function. In general, multipronged, proactive recruitment strategies were more effective than traditional, passive methods in reaching participants with varying degrees of cognitive impairment. The outcome of this study suggests that successful recruitment of such populations involves gaining the support of staff at relevant community organizations, informing community members (including older adults and their family members) of the project and the importance of oral health, and making data collection sites accessible for older adults.

The objectives of this study were (1) to compare the in vivo survival rates of orthodontic brackets bonded with a resin-modified glass ionomer adhesive (Fuji Ortho LC; GC America, Alsip, Ill) after conditioning with 10% polyacrylic acid and a conventional resin adhesive (Light Bond; Reliance Orthodontic Products, Itasca, Ill) bonded with 37% phosphoric acid, (2) to compare the in vitro bond shear/peel bond strength between the 2 adhesives, (3) to determine the mode of bracket failure in the in vivo and in vitro tests according to the adhesive remnant index (ARI), and (4) to compare the changes in surface morphology of enamel surface after etching or conditioning with 10% polyacrylic acid, with scanning electron microscopy. In the in vitro study, 50 extracted premolars were randomly divided into 4 groups: brackets bonded with Fuji Ortho LC or Light Bond adhesive that were debonded after either 30 minutes or 24 hours. Bond strengths were determined with a testing machine at a crosshead speed of 1 mm/min. Data were analyzed with analysis of variance and a paired Student t test. The in vivo study consisted of 398 teeth that were randomly bonded with Fuji Ortho LC or Light Bond adhesive in 22 subjects with the split-mouth technique. Bracket survival rates and distribution were followed for 1.3 years. Data were analyzed with Kaplan-Meier product-limit estimates of survivorship function. The in vitro study results showed significant differences (P

Objectives. The objectives of this study were (1) to develop polyacid formulations through the incorporation of amino acid-derived monomers with carboxylic acid groups at various distances away from the polymer backbone to allow for greater flexibility, less rigid ionic cluster formation and improved solubility, and (2) to test selected physical and handling properties of experimental ionomers with a conventional glass ionomer as a control. Methods. The polycarboxylic acids prepared and used in the glass ionomer formulation in this study included N-acryloylglutamic acid (AGA) and N-acryloyl-6-aminocaproic acid (AACA)-modified acrylic aciditaconic acid copolymers, where the acrylic acid: itaconic acid:amino acid monomers were combined in different proportions. The characterization and purity of the monomers were determined by FTIR and their melting points. The characterization of synthesized polymers included molecular weight and relative viscosity determinations. The compressive strengths, diametral tensile strengths, flexural strengths and fracture toughness of the experimental ionomers and a commercially available ionomer (control) were measured after storage in water, at 37°C for 1 h or 7 d. The working times and setting times of the experimental ionomers were compared to the control specimens. Separate analysis of variance and Tukey's tests were used to study the statistical significance of the physical strength parameters as a function of materials and storage times. Results. Significant increases (p

This study investigated whether oral hygiene self-care behavior differs between genders in older adults in Appalachia, a geographic area with significant oral health concerns. Identify ing the practices of older adults may provide valuable information for designing interventions and improving overall oral health outcomes.As part of a larger, on-going study on cognition and oral health in later life in Appalachia, a sample of dentate, older adults without dementia aged 70 and above (n=245, 86 men and 159 women) received an oral assessment by either a dentist or dental hygienist. Psychometricians assessed cognition using a standardized battery of neuropsychological tests. They also administered the General Oral Health Assessment Index and conducted structured interviews concerning diet, oral hygiene practices, oral health, social support, income and years of education Results: Over 80% of women (n=128) and 52.3% of men (n=45) reported brushing their teeth twice daily. Multivariate logistic regression analysis was conducted, controlling for socioeconomic status, social support (i.e., frequency of contacting friends and relatives), general oral health assessment items, number of decayed, missing and filled surfaces, plaque index and having regular dental visits. The results showed that women reported more frequent tooth brushing than their male counterparts (OR=4.04, 95% CI:1.93,8.42).Older women in West Virginia had significantly better oral hygiene practices than older men, particularly regarding tooth brushing. Interventions are needed to improve older men's dental hygiene behaviors to improve overall oral health outcomes.

Older adults are susceptible to reduced saliva production related to certain medications, radiation and chronic conditions. Many of these people have many physical and oral health problems and limited access to dental care. The use of effective screening tools for xerostomia and hyposalivation would be helpful in identifying those at risk. The authors conducted a study to investigate the association between three measures of oral dryness: hyposalivation (low unstimulated salivary flow), self-reported xerostomia and clinically assessed dry mouth.The authors included a convenience sample of 252 nondemented and dentate West Virginia participants 70 years and older who were part of a larger study on oral health and cognition among older adults. Participants completed a self-reported xerostomia index, provided an unstipulated salivary sample and underwent an oral assessment for the study.Twenty-eight participants (11.1 percent) had hyposalivation, eight of whom reported having xerostomia (sensitivity=28.6 percent). Of the 43 participants who reported having xerostomia, only eight had hyposalivation (positive predictive value=18.6 percent). Hyposalivation and self-reported xerostomia were not significantly related. Clinically assessed dry mouth correlated modestly, but significantly, with hyposalivation and self-reported xerostomia.Obtaining routine unstimulated salivary flow rates in addition to self-reported information and oral evaluations may increase early detection of oral dryness, which would assist in implementing early interventions to improve patients' quality of life.Visually inspecting oral tissues for dryness and asking a patient if his or her mouth is dry are insufficient measures for clinicians to use to determine if the patient has hyposalivation. The authors recommend that clinicians determine the patient's unstimulated salivary flow rate.

A self-etching primer (SEP) saves valuable time by eliminating the many steps required to etch, rinse, and place a sealant before application of the adhesive and placement of the bracket. The purpose of this study was to compare the effects of a conventional etch and sealant (CES) and a SEP on enamel decalcification in vivo.Twenty-five patients who required comprehensive orthodontic treatment were included in this study. Before bonding, enamel surfaces were treated with either a CES (Light Bond, Reliance Orthodontic Products, Itasca, Ill) or a SEP (Transbond Plus, 3M Unitek, Monrovia, Calif) by using a split-arch technique. At the end of the observation period (18-24 months), the O'Leary plaque index was used to determine patients' oral-hygiene compliance, and enamel decalcification around the orthodontic bracket was scored based on the amount and severity of decalcification. Scanning electron microscopy images and x-ray spectrum analysis were performed to examine the etched pattern of the 2 bonding systems. Data were analyzed by using analysis of variance (ANOVA) and the Tukey-Kramer test; the confidence level was set at a significant level of P = 0.05.Significantly higher decalcification scores were found in the SEP group (27.5%) compared with the CES group (13.9%, P0.001). No significant differences were found in the decalcification scores for teeth in the maxillary and mandibular arches. Significant differences were found between level of hygiene and decalcification (P0.0001). Patients with fair or poor hygiene compliance had higher decalcification scores in the SEP group than in the CES group.Using a SEP might save chair time and improve cost-effectiveness, but it provides less resistance to enamel decalcification than a CES, especially in patients with poor oral hygiene.

The objective of this study was to compare the resistance to enamel demineralization between self-etching primer (SEP) and conventional sealant in vitro.A total of 120 molar sections were randomly assigned to 3 groups: SEP (Transbond Plus, 3M Unitek, Monrovia, Calif), sealant (Light Bond fluoride-releasing sealant, Reliance Orthodontic Products, Itasca, Ill), or control (no enamel treatment). SEP or sealant was applied following the manufacturer's recommendations. The tooth samples were exposed to rotary brushing for 2 minutes. A 2 x 2-mm window of sound enamel was created by using nail varnish. After 48 or 72 hours of acidic challenge with Ten Cate solution (pH 4.46), the samples were sectioned down to a thickness of 200 microm and stained with rhodomine B dye to evaluate lesions, lesion depths, area of lesions, and total fluorescence by using confocal microscopy. Statistical analyses were performed with 1-way analysis of variance (ANOVA) and Tukey-Kramer tests.The incidence of lesion was 50% in the sealant group and 100% in both the SEP and the control group. The lesion in the sealant group was present only when the sealant integrity was broken. Lesion depth (149.9 +/- 20.5 microm), area (636 +/- 90 x 10(2) microm(2)), and total fluorescence (252 +/- 83 x 10(4)) in the SEP group were similar to those in the controls. Lesion depth (107.6 +/- 45 microm), area (441 +/- 212 x 10(2) microm(2)), and fluorescence (160 +/- 103 x 10(4)) in the sealant group were significantly less than in the SEP and control groups (P0.05).These results suggest that neither sealant completely protects the teeth against enamel decalcification. The application of sealant provided protection in 50% of the samples, whereas the SEP provided no resistance to enamel demineralization. Protection from acid demineralization depends on the integrity of the sealant.

Introduction Technological advances have attempted to improve the standard of traditional x-ray imaging. ImageIQ software (LumenIQ, Bellingham, Wash) enhances conventional radiography by producing a computer-generated, enhanced 2-dimensional (2D) image, adding depth and detail. The software converts the scales of gray to topographic height values, which are easier for the eye to see. The purpose of this study was to determine whether the enhanced 2D renderings are as sensitive as traditional 2D radiographs for detecting periodontal defects in cadaver mandibles. Methods Periodontal defects were located and classified on 20 cadaver mandibles. These defects were radiographed, and computer-generated, enhanced 2D topographic renderings were made with ImageIQ software. A panel of evaluators was shown the 2D radiographs and the enhanced 2D renderings in random order. The evaluators classified the defects from these images. Results Significantly better agreement by the evaluators with the intrasurgical classification was found with the enhanced 2D rendering to view periodontal defects vs the traditional 2D x-ray. Enhanced 2D renderings improved the accuracy of radiographic periodontal defect classification by 14.3% over traditional 2D radiographs. Conclusions Computer generated, enhanced 2D renderings of conventional radiographs might provide a reliable diagnostic alternative to conventional 2D radiographs when attempting to classify periodontal defects.

Introduction: This study assessed in-vitro shear bond strength and in-vivo survival rate of orthodontic brackets bonded with either a halogen or a plasma arc light. Methods: Ninety extracted premolars were divided into 6 groups of 15. Stainless steel brackets were bonded to the teeth by using either a halogen light with a 20-second curing time or a plasma arc light with a 2-, 6-, or 10-second curing time. Brackets were debonded either within 30 minutes of bonding or after thermocycling for 24 hours. Bond strengths were tested on a testing machine at a crosshead speed of 1 mm/minute. The bracket failure interface was measured with a modified adhesive remnant index score. Data were analyzed by using ANOVA and Tukey-Kramer multiple comparison tests. For the in-vivo study, a split-arch design was used to determine the bracket-failure rate and distribution in 25 patients. The patients were followed for a mean period of 1.1 years (386 days). Survival analysis was carried out to compare the failure rates of the 2 techniques. Results: No significant differences in bond strengths were found 30 minutes after bonding between the halogen light (13.6 ± 3.8 MPa) and the plasma arc light with 2-, 6-, or 10-second curing times (9.6 ± 2.9, 14.2 ± 4.6, 16.0 ± 3.0 MPa, respectively). Similar bond strengths were also found between the halogen light with a 20-second (16.1 ± 3.6 MPa) curing time and plasma arc light with 6 seconds (18.2 ± 4.6 MPa) of curing time after 24 hours of thermocycling. For the in-vivo study, no significant difference was found in bracket failure rates between the 2 light sources (4.9% in both groups). No significant differences were found between ARI scores for the halogen light and the plasma arc light at either 30 minutes or 24 hours after debonding. Conclusions: These results indicate that the plasma arc light with a 6-second curing time can produce similar bond strength and bracket-failure rates as the halogen light that requires a longer curing time.

The principle of early treatment through well-planned extraction of primary teeth followed by removal of permanent teeth has stood the test of time. The objective of this article is to develop some simple guidelines for general dental practitioners to perform 'guidance of eruption' in malocclusion with severe crowding.

Lead, a ubiquitous environmental contaminant, has been shown to modulate various functions of the immune system and decrease host resistance to infectious disease. However, limited information is available concerning the direct effects of lead on the host immune response to an infectious agent after developmental exposure. The current study utilized chickens to examine the effect of embryonic lead exposure on immune and cellular responses during viral challenge. Sublethal doses of lead were introduced into fertilized Cornell K Strain White Leghorn chicken eggs via the air sac at day 5 or day 12 of embryonic development (designated as E5 and E12, respectively). Four-week-old female chickens were inoculated with infectious bronchitis virus (IBV) strain M41. Antibody titer to IBV, delayed-type hypersensitivity (DTH) response against bovine serum albumin (BSA), the absolute number and percentage of leukocyte subpopulations, and interferon-gamma (IFN-gamma)-like cytokine production by splenocytes were evaluated at 5-6 weeks of age. While antibody response to IBV in juvenile chicks was unaffected by the in ovo lead exposure, IFN-gamma-like cytokine production by splenocytes was significantly depressed following lead exposure at both developmental stages. In contrast with this pattern, the DTH response against BSA was unaffected following E5 exposure, but was significantly decreased after E12 exposure to lead. These changes were similar to those previously reported in chickens not exposed to IBV. While lead exposure at E5 induced significant changes in the percentage of circulating heterophils at 1 day postinfection (dpi), lead did not cause any change in relative leukocyte counts after E12 exposure. At 7 dpi, E5 lead exposure resulted in decreased absolute number and percentage of circulating lymphocytes, while total leukocyte counts, and the absolute number and percentage of circulating monocytes and heterophils were significantly reduced in E12 lead-exposed chickens. These results suggest that low-level exposure to lead has a direct effect on the developing chicken immune system, which is evident even during a postnatal infection. Furthermore, some of the changes were observed only when chicks were stressed by the viral infection. It appears that lead exposure during different stages of embryonic development is likely to result in different immunotoxic outcomes in juveniles.