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The effectiveness of chemotherapy in hepatocellular carcinoma (HCC) is restricted by chemo-resistance and systemic side effects. To improve the efficacy and safety of chemotherapeutics in HCC management, scientists have attempted to deliver these drugs to malignant tissues using targeted carriers as nanoparticles (NPs). Among the three types of NPs targeting (active, passive, and stimuli-responsive), active targeting is the most commonly investigated in HCC treatment. Despite the observed promising results so far, clinical research on nanomedicine targeting for HCC treatment still faces many challenges.These include batch-to-batch physicochemical properties' variations, limiting large scale production and insufficient data on human and environmental toxicities. This review summarized the characteristics of different nanocarriers, ligands, targeted receptors on HCC cells and provided recommendations to overcome the challenges, facing this novel line of treatment for HCC.

Medicinal plants are identified and used throughout human history; it has a great economic value especially in drugs discovery. Date palm pollen (DPP) is used traditionally in Sudan for treating sub-fertile male patients. Male infertility is heterogeneous group of disorders, most of them are idiopathic. This study is aimed to investigate the role of pharmaceutical preparation of DPP in amelioration of male sub fertility with detection of any possible adverse effects on the major body system functions, through blood picture, liver enzymes and kidney function. This study is a single group pretest-posttest experimental prospective comparative self-control. Sub-fertile men with Idiopathic oligoasthenozoospermia or azoospermia were received 500 mg capsules of DPP twice daily for three months after conducting their safety profiles to detect any toxic effects on hematological, hepatological and nephrological functions, Blood samples were taken from the patients for serum level of FSH (for azoospermic patients), FSH and Testosterone (for oligoasthenozoospermic patients). Finally, Semen sample have been obtained for computerized assisted semen analysis (CASA) report I and II. DPP administration induced significant increase (p≤0.001) in testosterone level (in oligoasthenozoospermic patients) and FSH level (in azoospermic patients). DPP induced significant changes (p≤0.001) towards improvement in the total and progressive sperm motility percentages measured in oligoasthenozoospermic patients by CASA dynamic analysis report I and II. The toxicological studies for DPP approved their safety use in human.

Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL)and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional down regulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4–11 xenograft mouse models, oral administration of CDKI-73resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML. Refereed/Peer-reviewed

Hydroxytyrosol (HYT) is one of the main alcoholic compounds of the olive leaves extract (OLE), which is known for its beneficial effects. This study aimed to investigate the effectiveness of olive leaves extract standardized with 25% hydroxytyrosol (OLES-25%HYT) in treatment of induced ulcerative colitis. Three groups of albino rats, were divided as following, group 1 (normal control), group 2 (induced ulcerative colitis and untreated) and group 3 (induced ulcerative colitis and treated with OLES-25%HYT). Colonic tissue samples were collected from all studied groups, the antioxidant activity for malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO) and nitric oxide (NO) were performed. The expression of pro-inflammatory cytokines, the apoptotic gene Bax and the anti-apoptotic gene Bcl2 was obtained in colon tissue to evaluate the OLES-25%HYT effect on ulcerative colitis. OLES-25%HYT showed effectiveness on reduction of mortality rate and disease activity index (DAI). Also, reduced oxidative stress and inflammation in colon tissue, OLES-25%HYT showed a significant reduction in colon MDA, MPO and NO levels and a significant elevation in SOD, CAT and GPX levels and cause down regulation of pro-inflammatory cytokines. Also, the apoptotic gene Bax downregulated and the anti-apoptotic gene Bcl2 upregulated as a result of the treatment compared to untreated induced ulcerative colitis group. OLES-25%HYT showed intestinal anti-inflammatory, antioxidants and anti-apoptotic effects in experimental models of ulcerative colitis.

Introduction Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18–49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54–5.02), frailty (CFS 8 versus 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1–3: odds ratio 7.00, CI 5.27–9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusion Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

Background: Remote Ischemic Conditioning (RIC) was found effective in stroke models, likely via increased endothelial nitric oxide (NO); yet RIC failed to improve clinical outcomes ( NCT02342522 ; NCT02189928 ). We anticipated that comorbidities neutralize the benefits of RIC in stroke. Hypothesis: NO-therapy but not RIC is vasculoprotective in hypertensive stroke. Methods: Aged (18±1-mo old) S100A1-hets mutant (S100A +/- ) and wild-type (WT) mice were used. As needed, mice were treated with RIC, s-nitrosoglutathione (GSNO) reductase inhibitor (GRI; 5 mg/kg nebulized once daily for 2-wks), GSNO (100-ug/kg; nebulized once daily at 2h post-TES), and/or intravenous thrombolysis (IVT; 10mg/kg at 4h post-TES). Stroke and outcome measures were performed as mentioned below. Statistical significance was determined at P &lt 0.05. Results: S100A +/- compared to WT-type mice showed significantly higher mean arterial pressure (MAP) and lower plasma-NO, supporting a hypertensive phenotype with endothelial dysfunction in S100A +/- mice. In photothrombotic stroke (PTS), RIC significantly improved cerebral blood flow (CBF), behavior and reduced infarction in WT but not in S100A +/- mice at 48h. GRI in S100A +/- mice enhanced plasma NO, improved behavior and CBF, and reduced infarction significantly as compared to vehicle-treated S100A +/- at 48h post-PTS. RIC with GRI did not produce additive protection in S100A +/- mice at 48h post-PTS, demonstrating that the preservation of NO-pool with GRI protects against stroke, but RIC is not effective to enhance this endogenous protection in hypertensive mice. Moreover, GSNO nebulization but not RIC enhanced PbtO 2 , reduced BBB-leakage and brain hemoglobin (Hb)-content at 24h after thromboembolic stroke with and without IVT. Conclusions: NO-therapies but not RIC is effective in hypertensive stroke. RIC- and NO- therapies need further validation in comorbid stroke before embarking on the clinical trial.

Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer. Refereed/Peer-reviewed

Category: Diabetes; Trauma Introduction/Purpose: Management of complex foot and ankle deformities secondary to charcot neuroathropathy represents a significant challenge. This is a consequence of medical co-morbidities, vascular disease, peripheral neuropathy, and immune compromise with the surgical challenges of progressive bony defomity and bone resorption. To combat these challenges ‘superconstructs’ have been developed to improve fixation. These aim for fusion beyond the zone of injury with adequate deformity correction all whilst maintaining viability of the soft tissue envelope and mechanical function. This can be achieved with internal fixation using indication specific plates and beaming techniques, external fixation with a circular frame or a combination of the two. The aim of this study was to evaluate of a tertiary referral hospital in the operative management of charcot neuroarthopathy. Methods: This is a retrospective two surgeon case series with all cases jointly operated upon. Cases were identified from a locally held diabetic patient registry as those undergoing charcot foot and ankle reconstruction from 2017 to 2019. No exclusion criteria were outlined. Patient demographics and co-morbidities were collected, pre-op radiological markers (meary’s angle) measured and repeated at 6 weeks and one year. Pre-op radiographs were classifed accroding to brodsky classification. Patient outcomes were recorded of amputation, mortality, ulcer recurrence, reported pain, stable heel, ability to ambulate, need for revision surgery, need for prolonged antibiotics, fusion and surgical complications. PROMS were requested and still awaited at time of submission. Results: Eleven Cases were identified from ten patients, all were included for analysis. Three patients had internal fixation, two had external fixation and six had combined internal with external fixation. Eight patients were Brodsky 1, two patients were Brodsky 3 and one patient was Brodsky 2. Limb salvage was 100% with nil amputations, mortality 0%, ulcer recurrence 0%, 100% improved pain score, and 100% with a stable heel. Meary’s angle improved by a mean of 14o from -16o to -2o at 1 year. Fusion rate determined clinically and radiologically with X-ray was 100% with mean of 129 days and range of (360 - 52). Mean follow-up 454 days and range (547-417). Complications of 2 tibial fractures and 1 deep infection with delayed wound healing. Conclusion: The outcomes of using all three methods is positive with 100% limb salvage, 100% fusion rate, 100% ulcer free and maintenace of Meary’s angle at 1 year post op. We believe that combined internal and external fixation, not widely reported in the literature, is a good option in these cases. The complications reported here were in the first three patients undergoing said technique and represent a learning curve.

ECG beat type analysis is important in the detection of various heart diseases. The ECG beats give useful information about the status of the monitored heart condition. Up to now, various artificial intelligence-based methods have been proposed for ECG based heart failure detection. These methods were generally based on either time or frequency domain signal processing routines. In this study, we propose a different approach for ECG beat classification. The proposed approach is based on image processing. Thus, the initial step of the proposed work is converting the ECG beat signals to the ECG beat images. To do that, the ECG beat snapshots are initially saved as ECG beat images and then local feature descriptors are considered for feature extraction from ECG beat images. Eight local feature descriptors namely Local Binary Patterns, Frequency Decoded LBP, Quaternionic Local Ranking Binary Pattern, Binary Gabor Pattern, Local Phase Quantization, Binarized Statistical Image Features, CENsus TRansform hISTogram and Pyramid Histogram of Oriented Gradients are considered for feature extraction. The Support Vector Machines (SVM) classifier is used in the classification stage of the study. Linear, Quadratic, Cubic and Gaussian kernel functions are used in the SVM classifier. Five types of ECG beats from the MIT-BIH arrhythmia dataset are considered in experiments and the classification accuracy is used for performance measure. To construct a balanced training and test sets, 5000 and 10,000 ECG beat samples are randomly selected and are used in experiments in tenfold cross-validation fashion. The obtained results show that the proposed method is quite efficient where the calculated accuracy score is 99.9% and the comparisons with the state-of-the-art method show that the proposed method outperforms other methods.

This review investigated survival and alcoholic relapse following liver transplantation (LT) in patients with severe acute alcoholic hepatitis (AH) without 6 months of alcohol abstinence. All studies comparing acute AH patients undergoing LT with a control group were included. CENTRAL, MEDLINE, and Web of Science databases were searched. Survival benefits or odds ratios (OR) and 95% confidence intervals (CI) were assessed by meta-analyses using a random effects model. The study was registered in PROSPERO (CRD42017057971). According to the search results, two separate meta-analyses were performed: meta-analysis A compared early LT with medical therapy alone in patients with severe AH that were not responding to medical therapy and meta-analysis B compared LT outcome in patients with AH and chronic alcoholic cirrhosis (AC). The search yielded 2232 articles. Eight studies were included in the two meta-analyses—two studies in meta-analysis A and six studies in meta-analysis B. The two studies (n = 70) included in meta-analysis A revealed that 1-year patient survival was significantly higher in the LT group compared with the medical therapy–alone group (survival benefit, 15.88; 95% CI, 3.98–63.35; p

The discovery of novel anti-AML therapeutic agents is urgently needed, but the complex heterogeneity of the disease has so far hampered the development of a curative treatment. FLT3 inhibitors have shown therapeutic potential in clinical trials; but a monotherapy regimen has been associated with resistance mediated by the activation of parallel signalling circuitry, including MAPK and mTOR. Therefore, inhibiting a nexus of the two signalling pathways along with inhibition of FLT3 might be advantageous. Herein, we propose that a dual inhibition of FLT3 and Mnk would provide a better clinical option for AML patients compared to targeting FLT3 alone. Thus, a series of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines were prepared. Potent Mnk2 inhibitors, FLT3 inhibitors, and dual inhibitors of Mnk2 and FLT3 were identified and their anti-proliferative activities assessed against MV4-11 AML cell lines. Dual inhibition of FLT3 and Mnk2 caused the increased apoptotic cell death of MV4-11 cells compared to inhibition of FLT3 or Mnk2 alone. Refereed/Peer-reviewed

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.

Currently, the topic of natural language processing, morphological analysis, is a new emerging topics in the world. The main idea of morphological analysis may allow the identifi-cation of the literal origin of two words either root or seed and achieve the comparison to the original word. This paper de-scribes a new idea related to standard miniaturization ap-proach for Arabic morphological analysis. This approach based on regular noun morphological automaton technique (RNMT). The proposed algorithm focuses on a morphological regular abstractive noun (singular masculine) with length 3, 4 and 5 letters, which in turn, produce a special type of morpho-logical miniaturization that is based on the concept of world analysis and restructure according to morphine scales. This aspect contribute to develop the Arabic morphological minia-turization, by developing the standardization aspect. It can be exploited by NLP applications like syntactic and semantic analysis, information retrieval, machine translation and ortho-graphical correction. The result reveals that the proposed algo-rithm is anew attempt in Arabic language) Morphological analysis (and it is perfectly work on research sample, however, doesn’t recognize between the enter words if it noun or verb.

SukA«k are compliant alternative mode of financing with partial ownership in an asset, or project or business or an investment. The most commonly used such structure is a replication of the cash flows of conventional bonds, as in rental (ijarah) and these are listed in exchanges and traded on secondary markets in some 17 countries: Malaysia accounts for two-thirds of this market. The issues relating to these mostly new debt-like products are discussed in this chapter. Starting with general information, the author provides a literature review and describe how the market has developed in the last two decades. The reader should note the debt-taking principles surrounding this new form of debt-like products, which are aimed to provide specific funding needs of businesses at various stages of their needs. Endorsed by international institutions, this form of debt-taking is considered much safer than the mainstream practices that is based on the firm taking the risk, and the financier taking little risk.

Abstract This paper will discuss the coiled tubing (CT) fiber optic real-time telemetry system evolution for varied interventions performed in Saudi Arabia’s Ghawar field. The paper will show the benefits achieved with consistent improvement of the CT fiber optic real-time telemetry system, leading to better understanding of intervention and reservoir in real-time, optimization of treatment, opening new horizons and meeting huge successes. For years CT with fiber optic real-time telemetry, has been used in Saudi Arabia Ghawar field, whereas the initial version of the CT fiber optic real-time telemetry system consisted of 2-1/8 in BHA, comprising measurements of pressure, temperature, casing collar locator, gamma ray, tension and compression and distributed temperature sensing. Though the successes achieved from this system were remarkable, it was restricted to 2-bpm, had temperature limitations, and was not able to bear shocks and vibrations. As the time passed, interventions became more challenging. In order to meet well intervention objectives, a new tool was developed enabling higher pumping rates up to 8-bpm, and working temperatures of 300 °F. The challenge of bearing high shocks and vibrations was still not met, so a new was further designed to meet that objective. In the field, the new tool proved to be the most superior and advanced one, as the CT fiber optic real-time telemetry system gave high pump rates of 8-bpm, worked at temperatures of 350 °F, has a higher pressure rating, and was used in interventions where high shocks and vibrations were encountered. In addition to the above-mentioned CT fiber optic real-time telemetry system evolution, the system was enable to run the logging tools, leading to the development of a CT dedicated downhole flow measurement tool. These new tools provided the following advantages: optimize the treatment stages during a particular intervention, help operators gain a better understanding of the well and reservoir response during an intervention, assist in optimization of treatment strategy, and enable pre and post-treatment evaluation in minimum CT runs. This paper will explain the evolution of the CT fiber optic real-time telemetry system, and the significant impact the system has made to the oil and gas industry. The system enables CT interventions in a concise manner where decisions during a treatment are made using both surface and downhole parameters.

Purpose. To evaluate the impact of an educational workshop on parental knowledge, attitude, and perceived behavioral control regarding their child’s oral health. Materials and Methods. A one-time oral health education workshop including audio/visual and hands-on components was conducted by a trained dentist and bilingual community workers in community locations. Participants were African parents of children who had lived in Canada for less than ten years. The impact of the workshop was evaluated by a questionnaire developed based on the theory of planned behavior. Results. A total of 105 parents participated in this study. Participants were mainly mothers (mean age 35.03±5.4 years) who came to Canada as refugee (77.1%) and had below high school education (70%). Paired t-test showed a significant difference in participants’ knowledge of caries, preventive measures, and benefits of regular dental visits after the workshop (P value<0.05). A significant improvement was also found in parental attitudes toward preventive measures and their perceived behavioral control (P<0.05). Parents’ intention to take their child to a dentist within six months significantly altered after the workshop (P value<0.05). Conclusions. A one-time hands-on training was effective in improving parental knowledge, attitude, perceived behavioral control, and intention with respect to their child’s oral health and preventive dental visits in African immigrants.

Purpose It has been debated whether the Le Fort III procedure using distraction osteogenesis (LFIII-DO) reduces the risk of postintervention relapse compared with conventional Le Fort III (LFIII) osteotomy in the correction of syndromic midfacial hypoplasia. Our objective was to evaluate the short- and long-term stability of the bony structures after midfacial advancement using conventional LFIII osteotomy versus LFIII-DO in patients with syndromic midfacial hypoplasia. Materials and Methods We performed a systematic review of the published data. An electronic search of 10 databases was performed from their inception through June 2012. The reference lists of the relevant publications were also reviewed. Studies were considered for inclusion if they were longitudinal clinical studies with follow-up periods of at least 1 year after surgery (LFIII group) or at the end of the consolidation period (LFIII-DO group). Study selection, risk of bias assessment, and data extraction were performed in duplicate. The methodologic and clinical heterogeneity across the studies precluded combining the findings using meta-analyses. Results A total of 57 reports met the initial search criteria, and 12 reports were finally selected. The studies demonstrated a mean midfacial advancement of 8 to 12 mm in the LFIII group and 9 to 16 mm in the LFIII-DO group. For the LFIII group, horizontal short-term follow-up showed a maximal rate of relapse of 8.7 to 11.9% in 2 studies, with 1 study demonstrating a far more severe rate of maximal relapse of 50%. For the LFIII-DO procedure, the horizontal short-term relapse rate was 14.4% in 1 study, with the remainder demonstrating a rate of relapse of less than 10%. Moreover, 3 studies even showed additional advancement without any rate of relapse. Conclusions Current evidence suggests that conventional LFIII and LFIII-DO techniques can effectively advance the midface forward in patients with syndromic midfacial hypoplasia and have good to excellent stability, with a mild rate of relapse. However, the LFIII-DO technique appears to achieve a greater amount of advancement with a lower rate of relapse compared with the conventional LFIII technique.

Background: The pilonidal disease is a minor surgical pathology that has distressful complications. Many original and newer treatment modalities have been used in its management (including excisional and conservative surgical approaches). However, there is non-consensus on any one of them and the main reason is the significant recurrence rate. The objective of the study was to evaluate the excisional surgical modalities and conservative surgical approach in management the pilonidal disease.Methods: A prospective study enrolled 98 patients (80 males vs. 18 females) with chronic sacrococcygeal pilonidal disease. The ages range is 15-42 years. Group IA were treated by simple excision with primary closure, group IB by simple excision with Z- plasty and group II by conservative surgical approach. The wound complications (wound disruption and infection), length of hospital stays, recurrence rate, patients' satisfaction, and the cosmetic appearance were recorded.Results: The excision and Z-plasy has the least recurrence rate, wound complications rate and average time off work days. The simple excision with primary closure has the highest patient's cosmetic satisfaction. Conservative surgical approach has the worst results (recurrence rate 75%, wound infection rate 65%, 21 days average time off work and two days average length of hospital stay)..Conclusions: The Z-plasty is superior to other methods (has the least recurrence rate). The conservative treatment has non-encouraging results, we recommend it for patients unwilling excisional surgery.

Background: Perforated appendicitis is a serious complication of acute appendicitis that usually occurs due to over delay in presentation, diagnosis, and surgical treatment. Wound infection is one of the important sequelae of perforated appendicitis. Method of the wound closure in perforated appendicitis is a critical factor that affects the incidence of wound infection and there is continuing controversy about the best method.Methods: 362 patients with a diagnosis of acute appendicitis were enrolled in a prospective randomized study that extended over three years. The intraoperative gross pathological state of the appendix was recorded as either negative or uncomplicated or perforated appendicitis. The relationship between the wound infection with each one of the three methods of wound closure (primary closure, open wound with delayed primary closure and partial wound closure) had been reported. The hospital stays were recorded for each method.Results: 18.78% of appendectomy was appendicitis negative, 62.98% uncomplicated appendicitis and 18.23% with perforated appendicitis. In the perforated appendicitis cases, Primary wound closure was used in 36.36%, open method and delay primary closure in 18.18% and partial wound closure in 45.45%. The wound infection rates were 37.5%, 16.66% and 13.33% in primary wound closure, open wound with delayed primary closure and partial wound closure respectively. Length of hospital stays were 7 days, 8 days and 4 days respectively.Conclusions: partial wound closure is superior to other methods of wound closure, which are primary wound closure and open wound with delayed primary wound closure.

Treatment of breast cancer represents a major therapeutic challenge, and thus identification of new targeted therapy is of paramount importance. Anti-apoptotic proteins, BCL2 and MCL1, and oncoprotein c-MYC are implicated in evasion of apoptosis and resistance to chemotherapy in both triple-negative breast cancer (TNBC) and estrogen receptor-positive breast cancer (ER+ BC). Transcription of these oncogenic factors requires cyclin dependent kinase 9 (CDK9). CDK9 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAPII) and acts as a rate-limiting step of transcription. Thus, targeting CDK9 can reduce the expression of these proteins effectively and simultaneously, presenting a promising therapeutic strategy for breast cancer. Utilizing extensive medicinal chemistry and biochemical assays, we previously identified and developed LS007 as an orally bioavailable (F = 56% in cynomolgus monkey at 4 mg/kg), and nanomolar inhibitor of CDK9 (Ki = 4 nM). In vitro, inhibition of CDK9-mediated phosphorylation of RNAPII (pRNAPIIS2) by LS007 resulted in downregulation of BCL2, MCL1 and c-MYC and activation of PARP cleavage indicating apoptosis in breast cancer cells (TNBC: MDA-MB-231, Hs578T and ER+ BC: MCF-7, T47D). In vivo, LS007 was well tolerated in mice after oral administration (MTD = 50 mg/kg QD and 100 mg/kg Q3D). In MDA-MB-231 TNBC xenograft, by daily oral dosing at 25 mg/kg and 50 mg/kg LS007 significantly reduced tumor growth (p < 0.001) with T/C of 53 % and 35 %, respectively, on day 21, when compared to the vehicle dosed group. Similarly, in MCF-7 ER+ BC xenograft model, oral dosing of LS007 at 25 mg/kg QD, 50 mg/kg Q2D and 75 mg/kg Q3D showed significant tumor growth inhibition with T/C of 50 %, 60 % and 47 %, respectively, and increased in animal survival (p < 0.001) compared to vehicle control. It was safe in the xenograft models as there was no significant body weight loss or other overt toxicities. In addition, histological analysis of major organs (liver, kidney, heart, bone marrow and intestine) of the mice receiving LS007 showed no drug related toxicities. These results support for development of LS007 towards the clinical trials for the treatment of TNBC and ER+ BC. Citation Format: Muhammed Hamidur Rahaman, Yinghui Zhang, Md Saiful Islam, Gary Heinemann, Abel Tesfaye Anshabo, Hugo Albrecht, Robert Milne, Shudong Wang. LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4427.

Whether inflammatory cytokines affect the skeletal response to glucocorticoid (GC) treatment is unclear. Our objectives were to (1) identify the cytokine(s) elevated during exacerbations of inflammatory bowel disease (IBD); (2) determine whether the cytokine(s) identified in this way is related to systemic GC sensitivity; and (3) examine whether cytokines and/or measures of GC sensitivity are related to changes in bone formation or resorption following GC therapy. We designed a combined cross-sectional and prospective study, including patients with active (n = 31) and inactive (n = 34) IBD as well as controls (n = 29). We assessed circulating concentrations of cytokines, PINP and betaCTX, as well as GC sensitivity in peripheral blood mononuclear cells. IL-6 was the only cytokine increased in active IBD, 2.35 (2.63) versus 1.64 (1.21) versus 1.31 (2.79) pg/microl active IBD, inactive IBD, and controls, respectively (median [interquartile range]) (P = 0.03, ANOVA). IL-6 was positively related to magnitude of GC sensitivity (beta = 0.02, 95% CI 0.008-0.04, P = 0.005). Following treatment with GC in active IBD, PINP decreased (P < 0.001), whereas betaCTX showed no significant change (P = 0.2). Subsequently, multiple regression analyses revealed that plasma IL-6 concentrations were inversely related to the extent of PINP suppression following GC (beta = 3.3, 95% CI 0.2-6.4, P = 0.04, adjusted for baseline PINP and duration of GC treatment), while no association was observed with GC sensitivity. In conclusion, IL-6 is elevated in active IBD and may protect against GC-induced suppression of bone formation via a mechanism which appears to be independent of systemic GC sensitivity.

Forced commutated cycloconverters (FCC's) have been used successfully as static frequency changers for low-to-medium frequency applications. The use of FCC's for high-frequency applications and, in particular, in the role of high-frequency links (HFL's) is investigated. Such links are widely used as intermediate stage circuits to provide simultaneous power conditioning and ohmic isolation. The investigation shows that suitable HFL circuit topologies do exist for any combination of input-to-output number of phases. It also shows that, through the use of appropriate switching techniques, it is possible to obtain HFL output voltage and input current waveforms with low harmonic content and insignificant amplitude derating.

• Mollaret's meningitis is a rare condition with a characteristic clinical and cerebrospinal fluid picture. In many ways it resembles recurrent hereditary polyserositis (familial Mediterranean fever) in its natural history, pattern of attacks, and response to colchicine. Association of the two conditions has been reported, so far, in two patients only. In our patient the symptoms of both conditions were induced by a metaraminol provocative infusion. We have previously introduced this as a specific diagnostic and confirmatory test for recurrent hereditary polyserositis. The possibility that the two conditions represent different manifestations of a single disease is therefore strengthened.