The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression.

MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). We found that the microRNA-212/132 cluster (Mirc19) is enriched in HSCs and is upregulated during aging. Both overexpression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow of mice led to rapid HSC cycling and depletion. A genetic deletion of Mirc19 in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-132 exerted its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrate that Mirc19 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified it as a potential target that might play a role in age-related hematopoietic defects.

Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer.

OBJECTIVE: Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC. METHODS: Starting at 4 weeks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed. RESULTS: Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice. CONCLUSION: Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

In vitro study to analyze reverse torque values of attachment screws with multiple loosening/tightening preload cycles.

PURPOSE: To determine the number of torque/reverse torque cycles attachment screws can withstand before fracture, and to record the magnitude of reverse torque values for each of the 10 cycles of screw tightening and loosening. MATERIALS AND METHODS: The testing assemblies consisted of 30 temporary cylinder/multiunit abutment/internal connection implants (10 each from Dentsply Sirona Astra, Biohorizons, and Zimmer Biomet Dental). The assemblies were inserted into resin blocks, and temporary cylinders were connected to the multiunit abutments with new attachment screws and torqued to the recommended preload (15 Ncm Dentsply Sirona Astra; 15 Ncm Biohorizons; 10 Ncm Zimmer Biomet Dental) using a digital torque gauge instrument (Model 3, MARK-10 Corporation, New York, USA) at room temperature without lubrication. After 24 h, the attachment screws were reverse torqued with the same instrument and the values were recorded. The torque/reverse torque cycles were repeated every 24 h for 10 days. Data were analyzed using mixed model analysis. A second test included torquing the used screws (30) until fracture or stripping occurred. The reverse torque values were recorded and compared with new screws that were torqued until fracture or stripping. A sample of used and new attachment screws from each assembly were viewed under both laser microscope (LEXT OLS4000, 3D Measuring Laser Microscope, Olympus) and scanning electron microscope (JEOL-JSM6510, Tokyo, Japan). Data were analyzed using t-test. RESULTS: Following 10 cycles of torquing and reverse torquing, the reverse torque values measured on day 10 were lesser compared with the reverse torque value measured on day 1 for 29/30 attachment screws (96.6%). According to the t-test used for the second test, the p-values among all three groups were ≥0.9 which were not statistically significant. CONCLUSION: The results of this study indicated that after 10 cycles of torquing and reverse torquing attachment screws, the reverse torque values decreased. There were no statistical differences between the magnitude of torque necessary to fracture new and used attachment screws.

Use of topic modeling to assess research trends in the journal Gynecologic Oncology.

STUDY OBJECTIVE: There is scant research identifying thematic trends within medical research. This work may provide insight into how a given field values certain topics. We assessed the feasibility of using a machine learning approach to determine the most common research themes published in Gynecologic Oncology over a thirty-year period and to subsequently evaluate how interest in these topics changed over time. METHODS: We retrieved the abstracts of all original research published in Gynecologic Oncology from 1990 to 2020 using PubMed. Abstract text was processed through a natural language processing algorithm and clustered into topical themes using latent Dirichlet allocation (LDA) prior to manual labeling. Topics were investigated for temporal trends. RESULTS: We retrieved 12,586 original research articles, of which 11,217 were evaluable for subsequent analysis. Twenty-three research topics were selected at the completion of topic modeling. The topics of basic science genetics, epidemiologic methods, and chemotherapy experienced the greatest increase over the time period, while postoperative outcomes, reproductive age cancer management, and cervical dysplasia experienced the greatest decline. Interest in basic science research remained relatively constant. Topics were additionally reviewed for words indicative of either surgical or medical therapy. Both surgical and medical topics saw increasing interest, with surgical topics experiencing a greater increase and representing a higher proportion of published topics. CONCLUSIONS: Topic modeling, a type of unsupervised machine learning, was successfully used to identify trends in research themes. The application of this technique provided insight into how the field of gynecologic oncology values the components of its scope of practice and therefore how it may choose to allocate grant funding, disseminate research, and participate in the public discourse.

Shear bond strength characteristics on surface treatment modalities of CAD-CAM resin polymers.

PURPOSE: The purpose of this in vitro study was to analyze the shear bond strength of composite resin to a commercially available high-performance polymer material for fixed, screw-retained full arch restorations. MATERIAL AND METHODS: A total of 135 computer-aided design and computer-aided manufacturing, high-performance polymer (HPP) blocks were cut and obtained from discs (Trilor 95, Harvest Dental, Brea, CA). The samples were 10 mm × 10 mm × 10 mm. The specimen surfaces were grouped as untreated (Group A), 50 µm Al2O3 (Group B), 110 µm Al2O3 (Group C), Rocatec (3 M, St. Paul, MN) activated with silica-modified alumina oxide treatment (Group D); and trimmed coarsely with a carbide bur (Group E). Group A samples were used as controls. After surface treatments, the specimens were gently cleansed with oil-free steam and alcohol wipes. Surface conditioning was performed on all physically treated samples.  The manufacturer's recommendations were followed for bonding composite resin to the samples with light-cured Visio.link (Bredent, Chesterfield, UK). Cylinders were veneered with composite resins (diameter 5 mm, height 4 mm) and polymerized on the specimen surfaces through plastic tubes. Twenty-seven specimens were used for each testing group and aging tests were performed. The experimental samples were thermocycled.  Shear bond strength and scanning electron microscopic tests were performed. Means and standard deviations were calculated.  Statistical analysis was performed with post-hoc Tukey tests. RESULTS: Statistical analysis revealed that there was a significant difference between the groups (p<0.001). The highest shear bond strengths were achieved for the specimens bonded with Visio.link without physical surface treatments (270.47 MPa). The lowest bond strengths were found for specimen surfaces abraded with 110 µm Al2O3 (117.03 Mpa) CONCLUSIONS: The results of this laboratory study indicated that the specimens used with Visio.link as provided by the manufacturer had the highest shear bond strengths between the composite resin and high-performance polymer test specimens. Modifications of the high-performance polymer surfaces with carbide burs did not change bonding strengths with the composite materials.

Conception after chemotherapy: post-chemotherapy method of conception and pregnancy outcomes in breast cancer patients.

PURPOSE: As the paradigm shifts towards improving cancer survivorship, an important concern for reproductive-aged women diagnosed with cancer is how their disease and its treatment will affect their future fertility. We sought to characterize pregnancy attempts and outcomes in breast cancer patients following chemotherapy. METHODS: We conducted a prospective cohort study of women diagnosed with breast cancer seen between 2010 and 2019. A questionnaire was administered following cancer treatment with questions regarding oncologic and reproductive history and attempts and method of conception. RESULTS: Of 181 participants, 46 (25.4%) attempted to conceive following chemotherapy. Thirty-five patients (76.1%) had return of ovarian function. Of those, 34 patients (mean age 32.8 years) first attempted to conceive by intercourse, and 22 (64.7%) became pregnant, resulting in 17 live births. Of the remaining 12 who did not successfully conceive through intercourse, eight went on to try other methods, resulting in five additional pregnancies and one live birth. Twelve patients (mean age 34.6 years) proceeded directly to ART; of those, eight (66.7%) became pregnant, resulting in six live births. CONCLUSION: In breast cancer patients with return of ovarian function after chemotherapy, half were able to conceive by intercourse alone. In order to maximize reproductive potential in patients who have return of ovarian function, providers should offer natural conception as a reasonable option prior to the use of cryopreserved tissue. For those who did not attempt to conceive on their own, the use of pre-treatment cryopreserved eggs or embryos had a high likelihood of success.

Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Attributable to a Human Myosin Regulatory Light Chain Mutation.

BACKGROUND: Restrictive cardiomyopathy is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy directed at the underlying cause. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of restrictive cardiomyopathy in a mouse model. METHODS: A short hairpin RNA (M7.8L) was selected from a pool for specificity and efficacy. Two groups of myosin regulatory light chain N47K transgenic mice were injected with M7.8L packaged in adeno-associated virus 9 at 3 days of age and 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine maximal oxygen uptake and left ventricular mass. At the end of treatment, heart, lung, liver, and kidney tissue was harvested to determine viral tropism and for transcriptomic and proteomic analysis. Cardiomyocytes were isolated for single-cell studies. RESULTS: A one-time injection of AAV9-M7.8L RNAi in 3-day-old humanized regulatory light chain mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed at 16 weeks postinjection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight, and attenuated a pathological increase in left ventricular mass. Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of contraction, relaxation, and calcium kinetics. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II and the transcription activator Brg1 were reduced, suggesting recovery toward a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts, and endogenous microRNAs were preserved, suggesting that the RNAi pathway was not saturated. CONCLUSIONS: Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed towards human restrictive cardiomyopathy. This is a promising step toward targeted therapy for a prevalent human disease.

Fertility preservation before breast cancer treatment appears unlikely to affect disease-free survival at a median follow-up of 43 months after fertility-preservation consultation.

BACKGROUND: The objective of this study was to determine whether fertility preservation (FP) with oocyte/embryo cryopreservation is associated with differences in disease-free survival (DFS). METHODS: This retrospective study included patients aged 18 to 45 who were diagnosed with invasive breast cancer between 2007 and 2017 and were seen for FP consultation at a university fertility center before cancer treatment. The primary endpoint, DFS, was defined as the time from FP consultation until patients developed a locoregional recurrence, distant metastasis, a contralateral breast tumor, or a new primary malignancy. DFS was compared for FP versus no FP using Kaplan-Meier survival estimates and Cox proportional-hazard regression analysis. RESULTS: The study included 329 women, with 207 (63%) in the FP group and 122 (37%) in the no FP group. Patients who underwent FP had more aggressive initial disease profiles than those in the no FP group. In addition, they were younger (35 vs 37 years; P = .009), more often had stage II or III disease (67% vs 55%; P = .03), and had higher rates of requiring chemotherapy (77% vs 65%; P = .01). Over a median follow-up of 43 months, the rates of DFS were similar among patients in the FP group and the no FP group (93% vs 94%, respectively; hazard ratio [HR] 0.7; 95% CI, 0.3-1.7). Positive ER status (79% vs 83%; P = .38), neoadjuvant chemotherapy (41% vs 48%; P = .32), ER-positive DFS (HR, 0.4; 95% CI, 0.1-1.6), and neoadjuvant chemotherapy DFS (HR, 1.4; 95% CI, 0.2-9.1) were similar in the FP and no FP groups, respectively. CONCLUSIONS: At a median follow-up of 43 months, FP appears unlikely to affect DFS, even in the setting of tumors with positive ER status or treatment with neoadjuvant chemotherapy (in which the tumor remains in situ during FP).

Prosthetic rehabilitation of a maxillary defect with a bone anchored prosthesis: A clinical report.

Mucormycosis is an opportunistic fungal infection that frequently infects sinuses, brain, or lungs and arises mostly in immunocompromised patients. Although its occurrence in the maxilla is rare, debridement and resection of the infected and necrotic area is often the best treatment but usually results in an extensive maxillary defect. Protocols for prosthetic obturation versus microvascular reconstruction have been established and used effectively in tertiary institutions for patients with such large defects. Aramany Class VI defects involving more than half of the palatal surface can be managed effectively by surgical reconstruction using microvascular free flaps as a platform for supporting bone-anchored prostheses. Providing fixed prostheses may offer advantages over a conventional obturator prosthesis in terms of hygiene, function, and esthetics. Nonetheless, fixed prostheses retained by endosseous implants in patients with reconstructive osteomyocutaneous flaps often require a sequential team approach by the surgeon and prosthodontist. This clinical report describes the reconstruction of a maxilla by using a scapular free flap with subsequent prosthetic rehabilitation in a patient with maxillary sinus infection secondary to mucormycosis.

Association Between Early Implant Failure and Prosthodontic Characteristics.

PURPOSE: To identify associations between early implant failure and prosthodontic characteristics that could be used to guide subsequent continuous quality improvement efforts of patient care. MATERIALS AND METHODS: An implant-level analysis was performed in which data were abstracted from a prospective clinical database of all adult patients treated with implants and followed up from January 2000 through December 2014 at the Department of Dental Specialties at Mayo Clinic in Rochester, Minnesota. These data were used to determine time to implant failure. Associations between prosthodontic characteristics and early implant failure were evaluated with Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 8762 implants in 2787 patients, 395 (4.5%) failed within the first year of placement at a mean (SD) of 127 (97) days (range, 2-364 days). Univariable analysis showed no associations between early implant failure and use of a cover screw, prosthesis, or definitive or provisional prosthesis at implant placement. Three of 25 single crowns failed, and use of a single crown was significantly associated with early implant failure (HR, 3.94; 95% CI, 1.08-14.35; P = 0.04). This study identified no significant associations between prosthodontic characteristics identified after implant placement and early implant failure. CONCLUSIONS: Use of a prosthesis at implant placement, use of a definitive or provisional prosthesis, and early mechanical complications were not associated with increased risk of early implant failure. Quality improvement efforts should focus on aspects of decision making that aim to decrease surgical complications.

Random start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer.

STUDY QUESTION: Is random start ovarian stimulation associated with delays in initiation of neoadjuvant chemotherapy for breast cancer? SUMMARY ANSWER: Among women who complete fertility preservation (FP) consultation, random start ovarian stimulation is unlikely to delay time to initiation of neoadjuvant chemotherapy start. WHAT IS KNOWN ALREADY: Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and random start ovarian stimulation is an increasingly-utilized modality for FP. While conventional ovarian stimulation does not appear to delay starting adjuvant chemotherapy, the relationship between random start ovarian stimulation and neoadjuvant chemotherapy start is not well-understood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of all women seen between from January 2011 to April 2017 for FP consultation prior to starting neoadjuvant chemotherapy for breast cancer. PARTICIPANTS/MATERIALS, SETTING, METHODS: A chart-review was performed. Study inclusion criteria were female sex; age 18-45; non-metastatic breast cancer diagnosis; underwent FP consultation; underwent neoadjuvant chemotherapy. Referrals for FP evaluation came from a regional referral base of oncology clinics. Various time-points related to cancer diagnosis, FP or chemotherapy were obtained from medical record review. We compared time-points between those who underwent ovarian stimulation for FP versus those who did not using T-tests and linear modeling. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 89 women who had FP consultation prior to neoadjuvant chemotherapy were identified. Sixty-seven percent underwent ovarian stimulation prior to cancer treatment and 33% did not. Women who underwent ovarian stimulation were similar in parity and clinical cancer stage to those who did not. Overall, the average time from cancer diagnosis to chemotherapy start was similar between the group that did undergo ovarian stimulation and those who did not (38.1 ± 11.3 versus 39.4 ± 18.5 days, P = 0.672). Those that underwent ovarian stimulation were referred 9.4 ± 6.8 days after diagnosis versus 17.9 ± 15.3 days for those who did not undergo ovarian stimulation (P < 0.001). LIMITATIONS REASONS FOR CAUTION: Retrospective study with potential for selection bias among those who underwent ovarian stimulation versus those who did not. Reasons for caution include the possibility of unmeasured differences among those who did and did not undergo ovarian stimulation, including: patients' and providers' perceptions of the urgency to start chemotherapy, ongoing oncology work-up and treatment planning, FP decision-making, and the pursuit of second and third opinions. The difference in time from referral to FP consultation may have also influenced patients' decisions about whether to undergo ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS: In this study, FP with random start ovarian stimulation was not associated with a delay cancer treatment in the neoadjuvant setting, so long as there was a prompt FP referral. Patients undergoing neoadjuvant chemotherapy should be informed of these findings to avoid unnecessary anxiety due to concern for delays. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by departmental research funding within the University of California, San Francisco Department of Obstetrics, Gynecology and Reproductive Sciences. There are no conflicts of interest to declare.

Long-term hormonal contraceptive use is associated with a reversible suppression of antral follicle count and a break from hormonal contraception may improve oocyte yield.

PURPOSE: Unlike infertility, patients presenting for fertility preservation (FP) are often using combined hormonal contraceptives (CHC). We studied whether long-term (≥6 months) CHC use is associated with reversible suppression of antral follicle count (AFC). METHODS: This is a longitudinal study of FP cycles from 2012 to 2016. We studied three groups: those without CHC exposure (NO CHC), those with CHC usage with a CHC break (BREAK), and without a break (NO BREAK) prior to ovarian stimulation. We assessed ovarian reserve by AFC at initial consultation and discussed the possibility of CHC suppression of AFC. Patients chose between ovarian stimulation with no CHC break versus ovarian stimulation after a CHC break. AFC was measured serially in the BREAK group. We assessed whether AFC suppression was reversed in the BREAK group. Total oocyte yield was compared among the NO CHC, BREAK, and NO BREAK groups. T tests, ANOVA, and linear/logistic regressions were used. RESULTS: Seven hundred forty-three women underwent FP. Twenty-one percent (n = 154) were taking long-term CHC (≥6 months). AFC suppression was more likely with CHC use (OR 1.6, 95% CI 1.1-2.4, P = 0.011). The BREAK group (n = 79) stopped CHC for an average of 4 months. AFC improvement started at 1 month and plateaued at approximately 6- to 7-month break. The BREAK group had approximately twice as many oocytes per initial AFC as NO BREAK (2.8 ± 3.8 vs. 1.4 ± 0.9, P < 0.001). CONCLUSIONS: When women present for FP on CHC, AFC may be suppressed. A CHC break of several months is associated with an increase in AFC and a potential improvement in overall egg yield.

A cephalometric analysis of Class II dentate subjects to establish a formula to determine the occlusal plane in Class II edentate subjects: A neo adjunct.

PURPOSE: Occlusal plane (OP) differs considerably in participants with skeletal Class I and Class II participants. In this study, cephalometrics has been used to help in the determination of orientation of the OP utilizing the nonresorbable bony anatomic landmarks in skeletal Class II participants and an attempt has been made to predict and examine the OP in individuals with skeletal class II jaw relationship. MATERIALS AND METHODS: One hundred dentulous participants with skeletal Class II malocclusion who came to the hospital for correcting their jaw relationship participated in the study. Their right lateral cephalogram was taken using standardized procedures, and all the tracings were manually done by a single trained examiner. The cephalograms which were taken for the diagnostic purpose were utilized for the study, and the patient was not exposed to any unnecessary radiation. The numerical values obtained from the cephalograms were subjected to statistical analysis. Pearson's correlation of <0.001 was considered significant, and a linear regression analysis was performed to determine a formula which would help in the determination of orientation of the OP in Class II edentulous participants. RESULTS: Pearson's correlation coefficient and linear regression analysis were performed, and a high correlation was found between A2 and (A2 + B2)/(B2 + C2) with "r" value of 0.5. A medium correlation was found between D2 and (D2 + E2)/(E2 + F2) with "r" value of 0.42. The formula obtained for posterior reference frame through linear regression equation was y = 0.018* × +0.459 and the formula obtained for anterior reference frame was y1 = 0.011* × 1 + 0.497. It was hypothesized that by substituting these formulae in the cephalogram obtained from the Class II edentate individual, the OP can be obtained and verified. CONCLUSION: It was concluded that cephalometrics can be useful in examining the orientation of OP in skeletal Class II participants.

Versatility of PEEK as a fixed partial denture framework.

Materials used for fixed partial denture (FPD) frameworks have had properties of excellent strength, durability, and biocompatibility. Some of the materials which have been used till date include alloys, ceramics, and high-performance polymers such as zirconia, Ni-Cr, lithium disilicate, and so on. All these, though excellent, have their advantages and disadvantages. Hence, the search has always been on for a better material. One such material, which has made its foray into dentistry in the recent times, is polyetheretherketone (PEEK). It is a semicrystalline thermoplastic material. PEEK has an excellent chemical resistance and mechanical properties that are retained at high temperatures. The versatility of PEEK as a dental material for FPD framework was evaluated in this case report.

Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A.

MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.

Sulindac exhibits anti-proliferative and anti-invasive effects in uterine serous carcinoma cells.

PURPOSE: Uterine serous carcinoma (USC) is a highly aggressive and frequently recurring subtype of endometrial cancer with limited treatment options for advanced or recurrent stages. Sulindac, a classic non-steroidal anti-inflammatory drug, has demonstrated anti-tumor activity in several pre-clinical tumor models. This study aims to evaluate the effect of sulindac on cell proliferation and invasion in USC cells. METHODS: Human USC cell lines ARK-1 and SPEC2 were treated with different concentrations of sulindac. Cell proliferation was assessed using MTT and colony formation assays. ELISA assays measured cellular stress, cleaved caspase 3 activity, antioxidant ability, and adhesion. Cell cycle arrest was evaluated by Cellometer. The invasive capability was detected by wound healing assay. Western blotting was used to analyze the changes in protein expression induced by sulindac. RESULTS: Exposure to sulindac decreased cellular viability in a dose-dependent manner in ARK-1 and SPEC2 cells. Sulindac effectively inhibited cell cycle progression, increased cellular stress, caused apoptosis, and reduced cell adhesion and invasion in USC cells. Additionally, sulindac decreased the expression of COX-2 and blocked phosphorylation of NF-κB induced by TNF-α. CONCLUSION: Sulindac is a potential therapeutic agent for USC that deserves further exploration in pre-clinical studies and potentially future clinical trials.

MicroRNA-125b potentiates macrophage activation.

MicroRNA (miR)-125b expression is modulated in macrophages in response to stimulatory cues. In this study, we report a functional role of miR-125b in macrophages. We found that miR-125b is enriched in macrophages compared with lymphoid cells and whole immune tissues. Enforced expression of miR-125b drives macrophages to adapt an activated morphology that is accompanied by increased costimulatory factor expression and elevated responsiveness to IFN-γ, whereas anti-miR-125b treatment decreases CD80 surface expression. To determine whether these alterations in cell signaling, gene expression, and morphology have functional consequences, we examined the ability of macrophages with enhanced miR-125b expression to present Ags and found that they better stimulate T cell activation than control macrophages. Further indicating increased function, these macrophages were more effective at killing EL4 tumor cells in vitro and in vivo. Moreover, miR-125b repressed IFN regulatory factor 4 (IRF4), and IRF4 knockdown in macrophages mimicked the miR-125b overexpression phenotype. In summary, our evidence suggests that miR-125b is at least partly responsible for generating the activated nature of macrophages, at least partially by reducing IRF4 levels, and potentiates the functional role of macrophages in inducing immune responses.

Large Publication Gap for Gynecologic Cancers in High-Impact Factor Journals.

OBJECTIVE: To analyze research publication trends in high-impact factor journals, comparing gynecologic cancers with other cancers from 2000 to 2018. METHODS: Abstracts from the 55 journals with the highest impact factors, as measured by Clarivate, from 2000 to 2018 were extracted from PubMed. We developed an algorithm to search the title of the abstract to determine whether the abstract was about cancer and to identify the cancer type. The algorithm was validated against the gold standard of human review in 1,143 abstracts. Article proportion was compared with site-specific incidence, mortality, and lethality from the National Cancer Institute's Surveillance, Epidemiology and End Results database using scatterplots and nonparametric Wilcoxon signed-rank test. RESULTS: We identified 128,377 articles; 31,045 (24.1%) were about cancer and 1,189 (3.8%) were about gynecologic cancers. Gynecologic cancers (ovarian, cervical, and uterine) were all poorly represented in high-impact factor journals compared with their incidence, mortality, and lethality. Ovarian, uterine, and cervical cancers ranked in the bottom half of Article-to-Lethality scores ( P <.01 for all comparisons). Analyses of the trends for gynecologic cancers over the past 18 years showed no change over time in Article-to-Lethality scores. Comparison of rankings by lethality with rankings by funding indicates relative underfunding of the gynecologic cancers. CONCLUSION: Research publications in high-impact factor journals by cancer site are not proportionate with individual cancer burden on society. Gynecologic cancers are significantly underrepresented in research publications relative to their disease burden, indicating a disparity that persists over the past 18 years. Relative underfunding of gynecologic cancers likely contributes to this publication gap.

Perioperative Use of Cefazolin and Indomethacin for Physical Examination-Indicated Cerclages to Improve Gestational Latency.

OBJECTIVE: To evaluate gestational latency in individuals who did and did not receive perioperative cefazolin and indomethacin after physical examination-indicated cerclage. METHODS: This is a retrospective cohort study of all pregnant women with a singleton gestation who underwent physical examination-indicated cerclage placement and delivered at Northwestern Memorial Hospital from 2009 to 2018. Physical examination-indicated cerclage was performed in the setting of painless cervical dilation of at least 1 cm between 16 0/7 and 23 6/7 weeks of gestation. After 2014, our practice universally implemented perioperative prophylaxis of cefazolin and indomethacin. Individuals were categorized based on exposure to perioperative prophylaxis. The primary outcome was pregnancy latency at least 28 days after cerclage placement. Secondary outcomes included median latency; median gestational age at delivery; preterm birth before 28 weeks of gestation; preterm prelabor rupture of membranes; chorioamnionitis; and median birth weight. Multivariable analyses were performed, as well as a sensitivity analysis using propensity score matching. RESULTS: Cerclages were placed in 142 people: 72 (50.7%) received perioperative prophylaxis. Baseline demographics were not significantly different between groups. On multivariable analyses, individuals who received perioperative prophylaxis had a higher incidence of achieving a pregnancy latency at 28 days or more (adjusted relative risk [aRR] 1.21, 95% CI 1.05-1.40). Individuals who received perioperative prophylaxis had a significant improvement in gestational latency (+17.8 days, 95% CI 1.4-34.2 days) and birth weight (+489.8 g, 95% CI 64.6-915.0 g), with no differences in other outcomes. On sensitivity analysis, individuals receiving perioperative prophylaxis had a higher incidence of achieving a pregnancy latency at 28 days or more, (aRR 1.17, 95% CI 1.01-1.36) with no differences in other outcomes. CONCLUSION: Perioperative use of cefazolin and indomethacin prophylaxis during physical examination-indicated cerclage placement is associated with a significant prolongation in gestational latency without an increase in incidence of chorioamnionitis.