HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding.

The energetic costs of duplicating chromatin are large and therefore likely depend on nutrient sensing checkpoints and metabolic inputs. By studying chromatin modifiers regulated by epithelial growth factor, we identified histone acetyltransferase 1 (HAT1) as an induced gene that enhances proliferation through coordinating histone production, acetylation, and glucose metabolism. In addition to its canonical role as a cytoplasmic histone H4 acetyltransferase, we isolated a HAT1-containing complex bound specifically at promoters of H4 genes. HAT1-dependent transcription of H4 genes required an acetate-sensitive promoter element. HAT1 expression was critical for S-phase progression and maintenance of H3 lysine 9 acetylation at proliferation-associated genes, including histone genes. Therefore, these data describe a feedforward circuit whereby HAT1 captures acetyl groups on nascent histones and drives H4 production by chromatin binding to support chromatin replication and acetylation. These findings have important implications for human disease, since high HAT1 levels associate with poor outcomes across multiple cancer types.

External beam radiation therapy combined with airway stenting leads to better survival in patients with malignant airway obstruction.

BACKGROUND AND OBJECTIVE: Malignant airway obstruction (MAO), a common complication of patients with advanced lung cancer, causes debilitating dyspnoea and poor quality of life. Two common interventions used in the treatment of MAO include bronchoscopy with airway stenting and external beam radiotherapy (EBRT). Data are limited regarding their clinical effectiveness and overall effect on survival. METHODS: A retrospective chart review of patients treated with airway stenting and/or EBRT at the Johns Hopkins Hospital for MAO between July 2010 and January 2017 was reviewed. Demographics, performance status, cancer histology, therapeutic intervention and date of death were recorded. Survival was calculated using cox regression analysis. RESULTS: Of the 606 patients who were treated for MAO, 237 were identified as having MAO and included in the study. Sixty-eight patients underwent rigid bronchoscopy and stenting, 102 EBRT and 67 a combined approach. Patients who underwent stenting hand an increased hazard ratio (HR) of death in comparison to those who received combination therapy (HR: 2.12, 95% CI: 1.02, 4.39), while there was a trend towards significance in the EBRT alone group in comparison to the combination therapy group (HR: 1.62, 95% CI: 0.93, 2.83). CONCLUSION: In this retrospective analysis, combination therapy with stenting and EBRT led to better survival in comparison to stenting or EBRT alone. Prospective cohort trials are needed to confirm these results.

A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

PURPOSE/OBJECTIVE(S): Cranial radiation therapy (CRT) may disrupt the corpus callosum (CC), which plays an important role in basic motor and cognitive functions. The aim of this prospective longitudinal study was to assess changes in CC mid-sagittal areas, CC volumes, and performance on neuropsychological (NP) tests related to the CC in children following CRT. MATERIALS/METHODS: Twelve pediatric patients were treated with CRT for primary brain malignancies. Thirteen age-matched healthy volunteers served as controls. Brain MRIs and NP assessment emphasizing motor dexterity, processing speed, visuomotor integration, and working memory (visual and verbal) were performed at baseline and at 6, 15, and 27 months following completion of CRT. Linear mixed effects (LME) analyses were used to evaluate patient NP performance and changes in regional CC volumes (genu, anterior body, mid-body, posterior body, and splenium) and mid-sagittal areas over time and with radiation doses, correcting for age at CRT start. RESULTS: The mean age at CRT was 9.41 (range 1.2-15.7) years. The median prescription dose was 54 (range 18-59.4) Gy. LME analysis revealed a significant decrease in overall CC volumes over time (p < 0.00001), with no overall effect of radiation dose. Analysis of individual CC regions demonstrated a significant decrease in all regional volumes over time (p < 0.00001) in patients, with no effect of radiation dose. Only in the splenium was there a trend toward a dose-dependent effect (p = 0.093). Patients had significantly reduced NP performance across visits-most notably in motor dexterity and visual working memory (both p < 0.0001). CONCLUSIONS: These prospective data demonstrate a significant decrease in CC regional volumes after CRT, with associated decline in neurocognitive function, most notably in manual dexterity, attention, and working memory. Further prospective study of larger cohorts of patients is needed to establish the relationship between CRT dose, neuroanatomical, and functional changes in the CC.

Correction to: A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

AbstractThe published version of this article unfortunately contained an error. Author "E. Mark Mahone" has been published incorrectly by capturing "Mark Mahone" as family name when it should only be "Mahone". Given in this article is the corrected name.

Management options in locally advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma is a highly lethal cancer that is rarely curable at the time of presentation. Unfortunately, most patients are diagnosed with either metastatic or locally advanced disease, which is not amenable to surgery owing to the high likelihood of incomplete resection. Given the generally poor prognosis with propensity for metastatic failure greater than that for local failure, treatment options are variable, and include chemotherapy, radiotherapy, targeted therapies, and combinations thereof. This review summarizes the current evidence for definitive management of locally advanced pancreatic adenocarcinoma, as well as the role of palliative therapies. Future directions, including the development of predictive biomarkers and novel systemic agents, are also discussed.

Comparative Evaluation of Antimicrobial Effectiveness and Compressive Strength in Neem and Lemongrass-Modified Glass Ionomer Cement: An In Vitro Study.

Background Glass ionomer cement (GIC) demonstrates biocompatibility and fluoride ion release, indicating their potential to inhibit a wide range of bacteria, although this remains uncertain. Lemongrass and neem are recognized for their potent antimicrobial activity against numerous pathogenic microorganisms. The objective of the study is to evaluate the antimicrobial effectiveness and compressive strength of GIC modified with neem and lemongrass. Methodology Lemongrass and neem were incorporated into conventional GIC at varying concentrations. Group I - neem-modified GIC (0.5%, 1%, 2%), group II - lemongrass-modified GIC (0.5%, 1%, 2%), and group III (non-modified GIC as a control group). The disk-shaped specimens were then compared to unmodified GIC (control). Antimicrobial effectiveness was assessed using the minimal inhibitory concentration (MIC) assay against Streptococcus mutans and Lactobacillus. Compressive strength was assessed using a Universal Testing Machine, with a crosshead speed set to 0.5 mm per minute. Statistical analysis was conducted with a significance level set at p < 0.05. Results Neem modification displayed superior antimicrobial effectiveness against both Streptococcus mutans and Lactobacillus at all concentrations when compared to the control, with 2% showing the least mean value of 0.262. In contrast, lemongrass modification exhibited a significant difference in effectiveness against Streptococcus mutans but no difference against Lactobacillus. Neem modification demonstrated superior performance compared to lemongrass (p < 0.05). Both modified groups showed no significant impact on compressive strength. Conclusions Neem-modified GIC demonstrated the highest antimicrobial efficacy against Streptococcus mutans and Lactobacillus without altering its compressive strength. This suggests its potential as a promising alternative material in restorative dentistry. Additional in vivo investigations are needed to assess the extended-term effectiveness of the material.

Knowledge and awareness of the Klinefelter Syndrome among the dental students.

The presence of one or more extra X chromosomes in a male causes Klinefelter Syndrome (KS). KS affects 1 in 500-1 in 1000 men, while about half remain undiagnosed. KS is characterized by huge stature, increase in arm length, the feminine distribution of adipose tissues (including gynecomastia), less or pubic hair, infertility, hypotonia, reduced size of penis and less than average verbal IQ, struggle in learning and requirements for less specified speech therapy. KS is a primary testicular insufficiency with high levels of gonadotropin caused by a lack of pituitary gland feedback. The aim of the study is to assess the knowledge and awareness of the KS among the dental students. This cross-sectional survey was conducted among dental students of a private dental hospital. To evaluate the knowledge and awareness of the participants about KS, a self-administered questionnaire consisting of 10 questions was prepared. Percentage analysis and frequency analysis and percentage analysis were performed. A Chi-square test was done to assess the correlation using the SPSS software. In our study, most of the participants were aware of the KS. They also knew that the KS is caused due to the additional X chromosome. We would like to conclude that the dental students were much aware about the Klinefelter and they also had a thorough knowledge about it.

Overexpression of BASP1 Indicates a Poor Prognosis in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: Brain abundant membrane attached signal protein 1 (BASP1) was originally identified as a membrane and cytoplasmic protein. Recent studies have shown that BASP1 highly expressed in cancer and promoted the proliferation of cancer. However, the role of BASP1 in head and neck squamous cell carcinoma (HNSCC) is largely unknown.  Here, we performed a systematic data analysis to examine whether BASP1 can function as prognostic marker in HNSCC. METHODS: In this study, we used Oncomine, and UALCAN, databases to analyze the expression of BASP1 in HNSCC. We used Kaplan-Meier plotter to evaluate the effect of BASP1 on clinical prognosis. In addition, we also analyzed genetic alterations, interaction network, and functional enrichment of BASP1. RESULTS: BASP1 mRNA expression level was remarkably increased in HNSCC than in normal tissues (P=1.624e-12). Moreover, high BASP1 expression was significantly related to poor survival (p=0.00056) in HNSCC patients. In addition, BASP1 gene amplified in 5% of HNSCC patients which contributes to the overexpression of BASP1. CONCLUSIONS: These findings suggest that BASP1 was frequently amplified which contributes to the overexpression of BASP1, thereby promoting HNSCC progression. Thus, these results indicate that BASP1 might serve as a biomarker to predict the progression and prognosis of HNSCC patients.

Population-based utilities for upper extremity functions in the setting of tetraplegia.

PURPOSE: People with tetraplegia face substantial physical and financial hardships. Although upper extremity reconstruction has been advocated for people with tetraplegia, these procedures are markedly underused in the United States. Population-based preference evaluation of upper extremity reconstruction is important to quantify the value of these reconstructive procedures. This study sought to establish the preferences for 3 health states: tetraplegia, tetraplegia with corrected pinch function, and tetraplegia with corrected elbow extension function. METHODS: A computer-based, time trade-off survey was administered to a cohort of 81 able-bodied second-year medical students who served as a surrogate for the general public. This survey instrument has undergone pilot testing and has established face validity to evaluate the 3 health states of interest. Utilities were calculated based on an estimated 20 years of remaining life. RESULTS: The mean utility for the tetraplegic health state was low. On average, respondents gave up 10.8 +/- 5.0 out of a hypothetical 20 years for perfect health, for a utility of tetraplegia equal to 0.46. For recovery of pinch function, respondents gave up an average of 6.5 +/- 4.3 years, with a corresponding health utility of 0.68. For recovery of elbow extension function, respondents gave up an average of 7.6 +/- 4.5 years, with a corresponding health utility of 0.74. CONCLUSIONS: This study established the preferences for 2 upper extremity surgical interventions: tetraplegia with pinch and tetraplegia with elbow extension. The findings from this study place a high value on upper-limb reconstructive procedures with tetraplegia.

Study of hand signs in Judeo-Christian art.

Hand gestures play a crucial role in religious art. An examination of Judeo-Christian art finds an ecclesiastical language that is concealed in metaphors and expressed by unique hand gestures. Many of these hand signs convey messages that are not familiar to most people admiring these paintings. Investigating the history and classifying some of the predominant hand signs found in Judeo-Christian art might serve to stimulate discussion concerning the many nuances of symbolic art. This presentation examines the meaning behind 8 common hand signs in Judeo-Christian art.

Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy.

OBJECTIVES: Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS: We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS: Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION: PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.

A Group-Based Mobile Application to Increase Adherence in Exercise and Nutrition Programs: A Factorial Design Feasibility Study.

BACKGROUND: Novel methods of promoting self-monitoring and social support are needed to ensure long-term maintenance of behavior change. In this paper, we directly investigate the effects of group support in an exercise and nutrition program delivered by an mHealth application called Fittle. OBJECTIVE: Our first specific study aim was to explore whether social support improved adherence in wellness programs. Our second specific study aim was to assess whether media types (ePaper vs mobile) were associated with different levels of compliance and adherence to wellness programs. The third aim was to assess whether the use of an mHealth application led to positive changes to participants' eating behavior, physical activity, and stress level, compared to traditional paper-based programs. METHODS: A 2 × 2 (eg, Media: Mobile vs ePaper × Group Type: Team vs Solo) factorial design feasibility study was conducted. A sample of 124 volunteers who were interested in improving eating behavior, increasing physical activity, or reducing stress participated in this study. The study duration was 8 weeks. All groups were self-directed with no ongoing human input from the research team. RESULTS: Participants in ePaper conditions had higher attrition rates compared to participants in Mobile conditions, χ3(2)=9.96, P=.02 (N=124). Participants in Mobile conditions reported their compliance with a much higher frequency closer to the time of challenge activity completion (2-sample Kolmogorov-Smirnov test comparing distributions was highly significant-KS=0.33, P<.001 [N=63]). Participants in ePaper conditions had a much higher frequency of guessing while reporting as compared with those in Mobile conditions-χ1(2)=25.25, P<.001 (N=63). Together, these findings suggest that the mobile app allowed a more accurate method to report and track health behaviors over a longer period than traditional ePaper-based diaries or log books. There was a significant difference in the overall compliance score for Mobile-Solo (Mean [SD] 0.30 [0.39]) and Mobile-Team (Mean [SD] 0.49 [0.35]) conditions (t50.82=1.94, P=.05). This suggests that working in a team increased participants' overall compliance within Fittle. Survival analysis showed that participants assigned to Team conditions are 66% more likely to engage longer with mHealth app-based intervention than those assigned to the Solo condition. Overall, participants across all groups reported some positive changes in eating behavior, physical activity, and stress level; however, participants in the Mobile-Solo condition reported higher perceived stress levels at the end of the study. CONCLUSIONS: The team-based Fittle app is an acceptable and feasible wellness behavior change intervention and a full randomized controlled trial to investigate the efficacy of such an intervention is warranted.

Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation.

PURPOSE: Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. METHODS AND MATERIALS: All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. RESULTS: Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05). CONCLUSIONS: NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.

Text mining biomedical literature for discovering gene-to-gene relationships: a comparative study of algorithms.

Partitioning closely related genes into clusters has become an important element of practically all statistical analyses of microarray data. A number of computer algorithms have been developed for this task. Although these algorithms have demonstrated their usefulness for gene clustering, some basic problems remain. This paper describes our work on extracting functional keywords from MEDLINE for a set of genes that are isolated for further study from microarray experiments based on their differential expression patterns. The sharing of functional keywords among genes is used as a basis for clustering in a new approach called BEA-PARTITION in this paper. Functional keywords associated with genes were extracted from MEDLINE abstracts. We modified the Bond Energy Algorithm (BEA), which is widely accepted in psychology and database design but is virtually unknown in bioinformatics, to cluster genes by functional keyword associations. The results showed that BEA-PARTITION and hierarchical clustering algorithm outperformed k-means clustering and self-organizing map by correctly assigning 25 of 26 genes in a test set of four known gene groups. To evaluate the effectiveness of BEA-PARTITION for clustering genes identified by microarray profiles, 44 yeast genes that are differentially expressed during the cell cycle and have been widely studied in the literature were used as a second test set. Using established measures of cluster quality, the results produced by BEA-PARTITION had higher purity, lower entropy, and higher mutual information than those produced by k-means and self-organizing map. Whereas BEA-PARTITION and the hierarchical clustering produced similar quality of clusters, BEA-PARTITION provides clear cluster boundaries compared to the hierarchical clustering. BEA-PARTITION is simple to implement and provides a powerful approach to clustering genes or to any clustering problem where starting matrices are available from experimental observations.

Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.

There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal-regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition.

Poland's syndrome: current thoughts in the setting of a controversy.

Poland's syndrome is a rare congenital disorder that is characterized by hypoplasia of the pectoralis muscles and ipsilateral webbing of the fingers. The name of this condition pays homage to Dr. Alfred Poland of Guy's Hospital, who in 1841 described a case of these two deformities during the autopsy of a 27-year-old convict. An exploration of the historical series reveals a clear progression of knowledge about this syndrome, accumulated by scientists across Europe and America. As such, the name "Poland's syndrome" stands as a point of contention to those who oppose the injudicious use of eponyms in medicine. An analysis of the relevant literature reveals a stepwise understanding of what has come to be known as Poland's syndrome.

Evidence-based medicine: the fourth revolution in American medicine?

SUMMARY: The use of evidence has become a force in American medicine to improve the quality of health care. Funding decisions from payers will demand studies with high-level evidence to support many of the costly interventions in medicine. Plastic surgery is certainly not immune to this national tidal wave to revamp the health care system by embracing evidence-based medicine in our practices. In scientific contributions of plastic surgery research, application of evidence-based principles should enhance the care of all patients by relying on science rather than opinions. In this article, the genesis of evidence-based medicine is discussed to guide plastic surgery in this new revolution in American medicine.

Outcomes of pyrolytic carbon arthroplasty for the proximal interphalangeal joint.

BACKGROUND: Arthritis of the proximal interphalangeal joint is a debilitating condition commonly treated with arthroplasty. The pyrolytic carbon (pyrocarbon) implant has been developed for proximal interphalangeal joint arthroplasty in these patients. This prospective outcomes study evaluated the outcomes and complications of the pyrocarbon implant for the proximal interphalangeal joint. METHODS: Consecutive candidates for proximal interphalangeal joint arthroplasty with pyrocarbon implants were evaluated prospectively. Functional measurements and the Michigan Hand Outcomes Questionnaire were administered preoperatively and at 3, 6, and 12 months postoperatively. Preoperative means and 12-month postoperative means for all functional measures were compared using paired t tests and nonparametric Wilcoxon signed rank sum test, and effect size was reported for the Michigan Hand Outcomes Questionnaire. RESULTS: Fourteen patients treated with 21 implants were enrolled in the study. At the 12-month follow-up period, mean active arc of motion was 38 degrees, decreasing slightly from the preoperative value. Mean grip strength improved from 11.3 kg to 15.1 kg, although the difference was not statistically significant. Mean key pinch values improved significantly from 6.6 kg preoperatively to 9.2 kg at the 12-month follow-up (p = 0.03). Jebsen-Taylor test scores showed improvement, although not significantly. Changes in all Michigan Hand Outcomes Questionnaire domains showed a large effect size. Three patients experienced squeaking of the implant and three patients experienced dislocation of the pyrocarbon joint. CONCLUSION: The pyrocarbon implant for proximal interphalangeal joint arthroplasty shows encouraging results, primarily in patient satisfaction and pain relief, but is associated with complications related to implant dislocations, which required prolonged treatment with external fixators.