Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.

Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.

Cultural adaptation of the iSupport online training and support programme for caregivers of people with dementia in Castilla y León, Spain.

BACKGROUND: E-learning has shown to be an effective intervention in helping informal caregivers of people living with dementia. It has the potential to reach people living in remote areas, increasing service coverage. As a response to the demographic context in Spain associated with a higher percentage of ageing, depopulation, and the complexities of health service delivery in rural areas, this paper describes the cultural adaptation and co-design of the iSupport online training and support programme for Castilla y León, Spain, as a potential e-health intervention to mitigate these constraints. METHODS: The translation and cultural adaptation were performed following the WHO guidelines, with some adaptation due to the cultural context of Spain. Three focus groups were conducted with informal caregivers, health professionals, and a group of experts on cognitive impairment and dementia. The co-design process was performed as a Patient and Public Involvement activity with three groups consisting of people living with dementia, informal caregivers, rural population and experts on technology and dementia. RESULTS: A total of 435 suggestions were proposed for adaptation associated with erroneous terminology, rewording text/writing, grammatical or punctuation marks errors, and repeated information or need for additional content. Several recommendations were exposed during the co-design process: preference for interactive material such as videos or images, a forum to receive feedback from health care professionals and to leave satisfaction comments, availability in multiple platforms (e.g., tablet, laptop, mobile), slide format for information presentation, and availability to edit letter size and background colours. CONCLUSIONS: A culturally adapted version of the iSupport was developed for Castilla y León, Spain. The need for modification of words and expressions, information links to local resources websites, adjustments of characters' names and caregivers' scenarios, and additional content to some sections were recommended. Suggestions for the design should be taken into account for further adapted versions and platform developments.

Evaluation of Change in Radiographic Fractal Dimension around Dental Implants Placed with Low-Speed Drilling and Standard Drilling Protocols.

Osseointegration is a process that depends on a multitude of factors, including the type of drilling, whether biological or conventional. OBJECTIVE: Establish box-counting dimension values for radiological images in patients with implants placed with both drilling methods. MATERIAL AND METHOD: The sample included 129 implants corresponding to 50 patients. A double-blind study of data collection was carried out with the subsequent analysis of the fractal dimension as a comparative value of the state of the trabecular architecture. RESULTS: We found no significant differences (p ≥ 0.05) between the two study groups comparing both drilling techniques. The values for the conventional drilling technique are 0.24 ± 0.07 and for biological drilling: 0.19 ± 0.11 with a p-value of 0.767. CONCLUSIONS: The drilling technique does not influence the success of the procedure and the osseointegration process.

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AMs and MDMs from donors with COPD and healthy donors underwent functional, metabolic, and transcriptional profiling. Measurements and Main Results: We observed that AMs and MDMs from donors with COPD display a critical depletion in glycolytic- and mitochondrial respiration-derived energy reserves and an overreliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH-generating enzyme, ME1 (malic enzyme 1), a known target of the antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2). Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance, and recovery of macrophage function. Conclusions: In COPD, an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity, which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

Fission Yeast Rho1p-GEFs: From Polarity and Cell Wall Synthesis to Genome Stability.

Rho1p is a membrane-associated protein that belongs to the Rho family of small GTPases. These proteins coordinate processes such as actin remodelling and polarised secretion to maintain the shape and homeostasis of yeast cells. In response to extracellular stimuli, Rho1p undergoes conformational switching between a guanosine triphosphate (GTP)-bound active state and a guanosine diphosphate (GDP)-bound inactive state. Cycling is improved with guanine nucleotide exchange factor (GEF) activity necessary to activate signalling and GTPase activating protein (GAP) activity required for subsequent signal depletion. This review focuses on fission yeast Rho1p GEFs, Rgf1p, Rgf2p, and Rgf3p that belong to the family of DH-PH domain-containing Dbl-related GEFs. They are multi-domain proteins that detect biological signals that induce or inhibit their catalytic activity over Rho1p. Each of them activates Rho1p in different places and times. Rgf1p acts preferentially during polarised growth. Rgf2p is required for sporulation, and Rgf3p plays an essential function in septum synthesis. In addition, we outline the noncanonical roles of Rho1p-GEFs in genomic instability.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

Use of the Fractal Dimension to Differentiate Epithelium and Connective Tissue in Oral Leukoplakias.

BACKGROUND: Oral leukoplakia (OL) is considered one of the most common potentially malignant oral disorders (OPMD), with a verified increased risk of developing oral cancer. The identification of the dysplasia grade (low-high) is the only consolidated factor used to evaluate this risk. The objective of this study was to verify the role of the fractal dimension (FD) in assessing this dysplasia. METHODS: To begin, 29 OL and 10 normal oral mucosa (NOM) biopsies were retrieved for FD analysis of the epithelial (dime) and the connective (dimc) tissue. RESULTS: In the OL group, the median value of dime is higher (1.67, IQR = 0.12) than for the NOM group (1.56, IQR = 0.08), with statistically significant differences (Wilcoxon test, p = 0.0031). There were no differences in relation to dimc. Significant differences were observed between the non-dysplasia vs. high-grade (p = 0.0156) and low-grade vs. high-grade (p = 0.0049) groups. No significant differences were identified in relation to dimc for the different degrees of dysplasia. For a cut-off point of 1.44 of dime, a specificity of 96.6% was obtained, a sensitivity of 100%, and an AUC = 0.819 (p = 0.003). CONCLUSIONS: FD at the level of the epithelium may be used as a diagnostic tool in OL.

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.

A Stimulator of the Salivary Excretion Based on Physical Vibration of the Parotid Glands.

Oral dryness causes significant health problems both functional (difficulty speaking, chewing and swallowing) and structural in teeth (increased number of infections) and oral mucosa. The main objective of this study is to show an alternative treatment to help stimulate the salivary secretion thus improving the quality of life of the patient. In this study, a salivary stimulation equipment using vibrotactile stimuli is shown. The system has been placed bilaterally in the parotid glands and assessed the efficacy of the salivary secretion by sialometry before and after the stimulation. The new proposal is capable of stimulating salivary secretion, in a significative way after 7 minutes of use, at least in the cases analyzed, and fulfills low-cost, easy-to-use, and safe technical restrictions. In this setting, this paper suggests the performance of a deep clinical trial to measure the exact efficacy of the prototype and the times and frequencies needed to state the optimal treatment depending in each case.

An Advance Computing Numerical Heuristic of Nonlinear SIR Dengue Fever System Using the Morlet Wavelet Kernel.

This study is associated to solve the nonlinear SIR dengue fever system using a computational methodology by operating the neural networks based on the designed Morlet wavelet (MWNNs), global scheme as genetic algorithm (GA), and rapid local search scheme as interior-point algorithm (IPA), i.e., GA-IPA. The optimization of fitness function based on MWNNs is performed for solving the nonlinear SIR dengue fever system. This MWNNs-based fitness function is accessible using the differential system and initial conditions of the nonlinear SIR dengue fever system. The designed procedures based on the MWNN-GA-IPA are applied to solve the nonlinear SIR dengue fever system to check the exactness, precision, constancy, and efficiency. The achieved numerical form of the nonlinear SIR dengue fever system via MWNN-GA-IPA was compared with the Runge-Kutta numerical results that verify the significance of MWNN-GA-IPA. Moreover, statistical reflections through different measures for the nonlinear SIR dengue fever system endorse the precision and convergence of the computational MWNN-GA-IPA.

Solving an Infectious Disease Model considering Its Anatomical Variables with Stochastic Numerical Procedures.

The aim of the current work is to perform the numerical investigation of the infectious disease based on the nonlinear fractional order prey-predator model using the Levenberg-Marquardt backpropagation (LMB) based on the artificial neuron networks (ANNs), i.e., LMBNNs. The fractional prey-predator model is classified into three categories, the densities of the susceptible, infected prey, and predator populations. The statistics proportions for solving three different variations of the infectious disease based on the fractional prey-predator model are designated for training 80% and 10% for both validation and testing. The numerical actions are performed using the LMBNNs to solve the infectious disease based on the fractional prey-predator model, and comparison is performed using the database Adams-Bashforth-Moulton approach. The infectious disease based on the fractional prey-predator model is solved using the LMBNNs to reduce the mean square error (M.S.E). In order to validate the exactness, capability, consistency, and competence of the proposed LMBNNs, the numerical procedures using the correlation, M.S.E, regression, and error histograms are drawn.

Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events.

BACKGROUND & AIMS: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD. METHODS: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrell's C-index. RESULTS: FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrell's C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrell's C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 <1.30", those with "FIB4 ≥1.30 then VCTE <8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3-6.8), whereas the risk of LREs significantly increased in patients with "FIB4 ≥1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3-10.9), and even more for those with "FIB4 ≥1.30 then VCTE >12.0 kPa" (aHR 12.4; 95% CI 5.1-30.2). CONCLUSION: VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management. LAY SUMMARY: The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD.

Competency of Neural Networks for the Numerical Treatment of Nonlinear Host-Vector-Predator Model.

The aim of this work is to introduce a stochastic solver based on the Levenberg-Marquardt backpropagation neural networks (LMBNNs) for the nonlinear host-vector-predator model. The nonlinear host-vector-predator model is dependent upon five classes, susceptible/infected populations of host plant, susceptible/infected vectors population, and population of predator. The numerical performances through the LMBNN solver are observed for three different types of the nonlinear host-vector-predator model using the authentication, testing, sample data, and training. The proportions of these data are chosen as a larger part, i.e., 80% for training and 10% for validation and testing, respectively. The nonlinear host-vector-predator model is numerically treated through the LMBNNs, and comparative investigations have been performed using the reference solutions. The obtained results of the model are presented using the LMBNNs to reduce the mean square error (MSE). For the competence, exactness, consistency, and efficacy of the LMBNNs, the numerical results using the proportional measures through the MSE, error histograms (EHs), and regression/correlation are performed.

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.

The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

Detection of surface forces by the cell-wall mechanosensor Wsc1 in yeast.

Surface receptors of animal cells, such as integrins, promote mechanosensation by forming clusters as signaling hubs that transduce tensile forces. Walled cells of plants and fungi also feature surface sensors, with long extracellular domains that are embedded in their cell walls (CWs) and are thought to detect injuries and promote repair. How these sensors probe surface forces remains unknown. By studying the conserved CW sensor Wsc1 in fission yeast, we uncovered the formation of micrometer-sized clusters at sites of force application onto the CW. Clusters assembled within minutes of CW compression, in dose dependence with mechanical stress and disassembled upon relaxation. Our data support that Wsc1 accumulates to sites of enhanced mechanical stress through reduced lateral diffusivity, mediated by the binding of its extracellular WSC domain to CW polysaccharides, independent of canonical polarity, trafficking, and downstream CW regulatory pathways. Wsc1 may represent an autonomous module to detect and transduce local surface forces onto the CW.

The Role of the Cell Integrity Pathway in Septum Assembly in Yeast.

Cytokinesis divides a mother cell into two daughter cells at the end of each cell cycle and proceeds via the assembly and constriction of a contractile actomyosin ring (CAR). Ring constriction promotes division furrow ingression, after sister chromatids are segregated to opposing sides of the cleavage plane. Cytokinesis contributes to genome integrity because the cells that fail to complete cytokinesis often reduplicate their chromosomes. While in animal cells, the last steps of cytokinesis involve extracellular matrix remodelling and mid-body abscission, in yeast, CAR constriction is coupled to the synthesis of a polysaccharide septum. To preserve cell integrity during cytokinesis, fungal cells remodel their cell wall through signalling pathways that connect receptors to downstream effectors, initiating a cascade of biological signals. One of the best-studied signalling pathways is the cell wall integrity pathway (CWI) of the budding yeast Saccharomyces cerevisiae and its counterpart in the fission yeast Schizosaccharomyces pombe, the cell integrity pathway (CIP). Both are signal transduction pathways relying upon a cascade of MAP kinases. However, despite strong similarities in the assembly of the septa in both yeasts, there are significant mechanistic differences, including the relationship of this process with the cell integrity signalling pathways.

Evaluation of Quality of Life and Satisfaction in Patients with Fixed Prostheses on Zygomatic Implants Compared with the All-on-Four Concept: A Prospective Randomized Clinical Study.

Purpose: No published research has compared patients' quality of life and satisfaction with fixed prostheses supported by zygomatic implants with those supported by all-on-four prostheses. The aim of this study was to evaluate patients' quality of life and satisfaction with fixed prostheses on zygomatic implants compared with the all-on-four concept. Materials and Methods: A total of 80 patients with atrophic edentulous maxillae were randomized into two groups: Group 1 (rehabilitated with fixed prostheses supported by 2-4 zygomatic and 2-4 conventional implants in the anterior region) and Group 2 (fixed prostheses on four implants in the anterior region following an all-on-four concept). One year after placement of the definitive prostheses, patients completed OHIP-14 and satisfaction questionnaires. Results: In all seven domains of the OHIP-14 and in the overall scores, a worse quality of life was found in Group 2 patients, with statistically significant differences between the two groups (p ≤ 0.05). Patients with zygomatic implants were more satisfied with their prostheses, with a statistically significant difference (p < 0.001). Conclusions: According to the results of this study, rehabilitation of patients with edentulous atrophic maxillae with prostheses supported by zygomatic implants combined with anterior implants provided better patient quality of life and satisfaction than prostheses supported by four implants.

Impact of liver injury on the severity of COVID-19: a systematic review with meta-analysis.

BACKGROUND AND AIMS: SARS-CoV-2 is mainly a respiratory virus that has relevant systemic effects. We assessed the impact of baseline liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin) on COVID-19-related outcomes, including mortality, intensive care unit (ICU) admissions, and non-fatal severe complications. METHODS: after a systematic review of the relevant studies the odds ratio (OR), mean difference, sensitivity, specificity, and both positive and negative likelihood ratios were calculated for the prediction of relevant COVID-19 outcomes by performing a meta-analysis using fixed and random effects models. A Fagan nomogram was used to assess clinical usefulness. Heterogeneity was explored by sensitivity analysis and univariate meta-regression. RESULTS: twenty-six studies were included (22 studies and 5,271 patients for AST, 20 studies and 5,440 subjects for ALT, and nine studies and 3,542 patients for bilirubin). The outcomes assessed by these studies were: survival (n = 8), ICU admission (n = 4), and non-fatal severe complications (n = 16). AST > upper limit of normal (ULN) (OR: 3.10 [95 % CI, 2.61-3.68]), ALT > ULN (OR: 2.15 [95 % CI, 1.43-3.23]), and bilirubin > ULN (OR: 2.78 [95 % CI, 1.88-4.13]) were associated with an increased prevalence of severe complications with a specificity of 78 %, 77 %, and 94 %, respectively. The mean difference between mild and severe COVID-19 was 10.7 U/l (95 % CI, 5.8-15.6) for AST, 8 U/l (95 % CI, 1.0-15) for ALT, and 0.3 mg/dl (95 % CI, 0.16-0.45) for bilirubin. CONCLUSIONS: patients showing liver injury had a significantly higher risk of developing severe COVID-19 as compared to those with normal liver function tests at admission. We should include the assessment of AST, ALT, and total bilirubin (TB) routinely in the workup of patients affected by SARS-CoV-2 in order to predict those at risk of developing COVID-19-related outcomes.

In Vitro Study of Synergic Effect of Cisplatin and Low Molecular Weight Heparin on Oral Squamous Cell Carcinoma.

OBJECTIVES: To evaluate the possible synergic effect of cisplatin and low molecular weight heparin (LMWH) on oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Cisplatin and enoxaparin sodium, alone or in combination, were administered at doses of 1, 2, 4, 8 and 10 µM and 0.1, 0.5, 1, 5, 10, 50, and 100 µg/ml, respectively, to the H357 human OSCC line. The effects on cell viability and apoptosis were evaluated after 24, 48, and 72 h and on cell migration after 18 and 24 h. RESULTS: 10 µM concentration of cisplatin produced the greatest decrease in cell viability, with significant differences at 24 (p=0.009), 48 (p=0.001) and 72 h (p = 0.003); the 100 µg/ml dose of enoxaparin produced the greatest decrease in cell viability but without significant differences (p>0.05). When different concentrations of cisplatin and enoxaparin were combined, it was found that 100 µg/ml enoxaparin sodium produced the greatest synergic effect on cell viability reduction. In analyses of apoptosis and cell migration, it was found that the combination of cisplatin at 8 or 10 µM and 100 µg/ml enoxaparin produced a higher rate of apoptosis at 24, 48, and 72 h and a greater reduction in cell migration at 18 and 24 h. CONCLUSIONS: A combination of cisplatin and enoxaparin sodium shows a synergic effect that reduces cell viability and cell migration capacity and increases the apoptosis of human OSCC cells. CLINICAL RELEVANCE: Enoxaparin may be beneficial in chemotherapy for patients with OSCC; this finding requires further clinical and laboratory investigation.

A novel checkpoint pathway controls actomyosin ring constriction trigger in fission yeast.

In fission yeast, the septation initiation network (SIN) ensures temporal coordination between actomyosin ring (CAR) constriction with membrane ingression and septum synthesis. However, questions remain about CAR regulation under stress conditions. We show that Rgf1p (Rho1p GEF), participates in a delay of cytokinesis under cell wall stress (blankophor, BP). BP did not interfere with CAR assembly or the rate of CAR constriction, but did delay the onset of constriction in the wild type cells but not in the rgf1Δ cells. This delay was also abolished in the absence of Pmk1p, the MAPK of the cell integrity pathway (CIP), leading to premature abscission and a multi-septated phenotype. Moreover, cytokinesis delay correlates with maintained SIN signaling and depends on the SIN to be achieved. Thus, we propose that the CIP participates in a checkpoint, capable of triggering a CAR constriction delay through the SIN pathway to ensure that cytokinesis terminates successfully.