Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer.

Breast cancer (BC) has a high mortality rate and is one of the most common malignancies in the world. Initially, BC was considered non-immunogenic, but a paradigm shift occurred with the discovery of tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs) in the BC tumor microenvironment. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) immunotherapy has emerged as a treatment option for BC, but it has limitations, including suboptimal antitumor effects and toxicity. Research has demonstrated that anti-CTLA-4 combination therapies, such as Treg depletion, cancer vaccines, and modulation of the gut microbiome, are significantly more effective than CTLA-4 monoclonal antibody (mAB) monotherapy. Second-generation CTLA-4 antibodies are currently being developed to mitigate immune-related adverse events (irAEs) and augment antitumor efficacy. This review examines anti-CTLA-4 mAB in BC, both as monotherapy and in combination with other treatments, and sheds light on ongoing clinical trials, novel CTLA-4 therapeutic strategies, and potential utility of biomarkers in BC.

Experimental investigation and molecular simulations of quinone related compounds as COX/LOX inhibitors.

Quinone-containing compounds have risen as promising anti-inflammatory targets; however, very little research has been directed to investigate their potentials. Accordingly, the current study aimed to design and synthesize group of quinones bearing different substituents to investigate the effect of these functionalities on the anti-inflammatory activities of this important scaffold. The choice of these substituents was carefully done, varying from a directly attached heterocyclic ring to different aromatic moieties linked through a nitrogen spacer. Both in vitro and in vivo anti-inflammatory activities of the synthesized compounds were assessed relative to the positive standards: celecoxib and indomethacin. The in vitro enzymatic and transcription inhibitory actions of all the synthesized compounds were tested against cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1), and 5-lipoxygenase (LOX) and the in vivo gene expression of Interleukin-1, interleukin 10, and Tumor Necrosis Factor-α (TNF-α) were determined. The IC50 against COX-1 and COX-2 enzymes obtained by the immunoassay test revealed promising activities of sixteen compounds with selectivity indices higher than 100-fold COX-2 selectivity. Out of those, four compounds revealed selectivity indices comparable to celecoxib as a reference drug. Furthermore, all the tested compounds inhibited LOX with an IC50 in the range of 1.59-3.11 µM superior to that of the reference drug used; zileuton (IC50 = 3.50 µM). Consequently, these results highlight the promising LOX inhibitory activity of the tested compounds. The obtained in vivo paw edema results showed high inhibitory percentage for the compounds 9a, 9b, and 11a with the significant lower TNF-α relative mRNA expression for compounds 5a, 5d, 9a, 9b, 12d, and 12e. Finally, in silico docking of the most active compounds (5b, 5d, 9a, 9b) against COX2 enzymes presented an acceptable justification of the obtained in vitro inhibitory activities. As a conclusion, Compounds 5b, 5d, 9a, 9b, and 11b showed promising results and thus deserves further investigation.

Maternal supplementation of curcumin-olive oil nanocomposite improves uteroplacental blood flow, placental growth and antioxidant capacity in goats.

This experiment was designed to investigate the impact of curcumin-olive oil nanocomposite (CONC) supplementation on uteroplacental hemodynamics and ultrasonographic measurements as well as maternal oxidative status in midgestating goats. Twelve synchronized pregnant goats (85.58 ± 1.08 days of gestation; mean ± SD) were uniformly assigned to two groups (n = 6/group); the first group received daily oral supplementation of CONC (3 mg/kg body weight; nanocurcumin [NC] group) for 32 days, and the second group was offered physiological saline (control) following the NC group timeline. The goats of both groups were examined at 3-day intervals for middle uterine (MUA) and umbilical (UMA) arteries hemodynamics (pulsatility index [PI], resistive index [RI], systole/diastole [S/D] and blood flow rate [BFR]) and diameters, uteroplacental thickness (UPT), placentomes' diameter (PD) and echogenicity, steroid hormones (progesterone and estradiol 17ß), oxidative biomarkers (total antioxidant capacity [TAC], catalase [CAT], malondialdehyde [MDA]), nitric oxide (NO) and blood cells DNA integrity. The UPT (p = 0.012) and PD (p = 0.021) values were higher in the NC group than in their counterparts' control group (D11-32). There were increases in diameter (p = 0.021 and p = 0.012) and decreases (p = 0.021, p = 0.016 and p = 0.041 [MUA]; p = 0.015, p = 0.023 and p = 0.011 [UMA] respectively) in Doppler indices (PI, RI and S/D) of the MUA and UMA in the NC group compared to the control group (D14-32). On D20-32 (MUA) and D14-32 (UMA), the NC goats had higher BFR than the control group (p = 0.021, 0.018 respectively). The means of blood cells with fragmented DNA were lower (p = 0.022) in the NC group than in the control group on Days 8 and 21 postsupplementation. There were increases in CAT and NO (D20-32; p = 0.022 and p = 0.004 respectively), and TAC (D17-32; p = 0.007) levels in the NC goats compared to the control ones. The NC group had lower (p = 0.029) concentrations of MDA than the control group on Day 20 postsupplementation onward. In conclusion, oral supplementation of CONC improved uteroplacental blood flow and the antioxidant capacity of midgestating goats.

Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection.

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

Breaking New Ground in Palliative Care: Examining the Impact of Al Ain - Palliative Care Outreach Program on Patients With Advanced Cancer in the United Arab Emirates.

Introduction This study aimed to evaluate the effectiveness of the Palliative Outreach Program in improving the quality of palliative care for patients with advanced cancer in a Tertiary Hospital in the Al Ain region of the United Arab Emirates (UAE). Methods & Material One hundred patients who met the inclusion criteria were included in the study and administered the patient version of the Consumer Quality (CQ) Index Palliative Care Instrument to assess their perception of the quality of care they received. The demographics, diagnosis, and questionnaire responses were analyzed to determine the effectiveness of the Palliative Outreach Program. Results A total of one hundred patients met the criteria for the study. Most patients were above 50, female, female, Non-Emiratis, and had high school certificates. The top three cancer diagnoses were breast (22%), lung (15%), and head & neck (13%). The patients reported high levels of support from their caregivers regarding physical, psychological, and spiritual well-being, as well as information and expertise. The mean scores for most variables were favorable, except for information (mean = 2.9540, SD= 0.25082) and general appreciation (mean = 6.7150, sd = 0.82344). Overall, the patients rated the care they received positively, with high mean scores for physical/psychological well-being (mean = 3.4950, SD = 0.28668), autonomy (mean = 3.7667, SD= 0.28623), privacy (mean = 3.6490, SD = 0.23159), and spiritual well-being (mean =3.7500, SD = 0.54356). The patients would recommend their caregivers to others in similar situations. Discussion The findings demonstrate that the Palliative Outreach Program effectively improves the quality of palliative care for patients with advanced cancer in the UAE. The CQ Index Palliative Care Instrument proved a novel method for assessing palliative care quality from patients' perspectives. However, there is room for improvement in providing more favorable information and general appreciation outcomes. Caregivers should focus on all areas to enhance their physical/psychological well-being, autonomy, privacy, spiritual well-being, expertise, and general appreciation of their patients. Conclusion In conclusion, the Palliative Outreach Program is an effective intervention to improve the quality of palliative care for patients with advanced cancer in the UAE. The patients reported high levels of support from their caregivers in all aspects of care, except for information and general appreciation. These findings provide valuable insights into the effectiveness of palliative care interventions and highlight the need for continued efforts to improve the quality of care for patients with advanced cancer.

Current Downhole Corrosion Control Solutions and Trends in the Oil and Gas Industry: A Review.

In the oil and gas industry, the presence of aggressive fluids and gases can cause serious corrosion problems. Multiple solutions have been introduced to the industry to minimize corrosion occurrence probability in recent years. They include cathodic protection, utilization of advanced metallic grades, injection of corrosion inhibitors, replacement of the metal parts with composite solutions, and deposition of protective coatings. This paper will review the advances and developments in the design of corrosion protection solutions. The publication highlights crucial challenges in the oil and gas industry to be solved upon the development of corrosion protection methods. According to the stated challenges, existing protective systems are summarized with emphasis on the features that are essential for oil and gas production. Qualification of corrosion protection performance based on international industrial standards will be depicted in detail for each type of corrosion protection system. Forthcoming challenges for the engineering of next-generation materials for corrosion mitigation are discussed to highlight the trends and forecasts of emerging technology development. We will also discuss the advances in nanomaterial and smart material development, enhanced ecological regulations, and applications of complex multifunctional solutions for corrosion mitigation which have become of great importance in recent decades.

Awareness About Total Knee Arthroplasty Among Hail Population.

BACKGROUND: Knee joint osteoarthritis is the most common among older adults. The knee joint needs to be treated surgically. The prevalence of this disorder is believed to be higher than 40% among people over 60. OBJECTIVE: To study public awareness about total knee replacement among the Hail population and to explore the relationship between the level of awareness and different socio-demographic factors. METHODS: A cross-sectional study was carried out in Hail, Saudi Arabia, using an online self-administered questionnaire created via Google Forms. Collected data were coded, entered, and analyzed using the Statistical Package for Social Sciences (SPSS; Version 23). RESULTS: A total of 431 participants enrolled in the study, of which 242 (56.15%) were males and 189 (43.9%) were females. Out of a total of 34 points, the average awareness score was 15 ± 6 (range: 5-33), with a mean percentage of awareness of 44.1%. The most reported causes of total knee replacement were overweight or obesity (82.6%), aging (61%), and rheumatoid arthritis (45.2%). The most known symptoms were pain (85.6%) and clicking sounds during movements (64.7%). Regarding the knowledge about the treatment, both physiotherapy and weight reduction were mentioned by 290 (67.3%), exercise by 244 (56.6%), and surgical intervention by 177 (41.1%) participants. The purpose of knee replacement surgery was to relieve pain according to 357 (82.8%) participants, improve walking quality according to 257 (59.6%) participants, and be able to do prayers (while kneeling) according to 215 (49.9%) participants. The most reported reasons that might prevent the participants from undergoing knee replacement surgery were the pain after surgery (59.4%), unavailability of surgeons (35.5%), and general complications from anesthesia (37.4%). Moreover, 188 (43.6%) participants thought that knee osteoarthritis is diagnosed using magnetic resonance imaging (MRI). Educational level was found to be associated with awareness score (p = .012). Conversely, gender, nationality, residence, and history of chronic disease were not found to be associated with awareness about total knee replacement (p = .548, .357, .734, and .639, respectively). CONCLUSION: An average level of awareness and knowledge regarding total knee replacement was observed. Educational level was found to be significantly associated with this awareness.

Structural analysis of hERG channel blockers and the implications for drug design.

The repolarizing current (Ikr) produced by the hERG potassium channel forms a major component of the cardiac action potential and blocking this current by small molecule drugs can lead to life-threatening cardiotoxicity. Understanding the mechanisms of drug-mediated hERG inhibition is essential to develop a second generation of safe drugs, with minimal cardiotoxic effects. Although various computational tools and drug design guidelines have been developed to avoid binding of drugs to the hERG pore domain, there are many other aspects that are still open for investigation. This includes the use computational modelling to study the implications of hERG mutations on hERG structure and trafficking, the interactions of hERG with hERG chaperone proteins and with membrane-soluble molecules, the mechanisms of drugs that inhibit hERG trafficking and drugs that rescue hERG mutations. The plethora of available experimental data regarding all these aspects can guide the construction of much needed robust computational structural models to study these mechanisms for the rational design of safe drugs.

Impacts of selenium nanoparticles and spirulina alga to alleviate the deleterious effects of heat stress on reproductive efficiency, oxidative capacity and immunity of doe rabbits.

Effects of dietary inclusion of spirulina platensis (SP) and selenium nanoparticles (SeNPs) combination (SP-SeNPs) on the reproductive performance in vivo and in vitro, reproductive and metabolic hormones, hemato-bichemical parameters, oxidative stress, and immunity of heat-stressed doe rabbis were evaluated. All supplements significantly increased live litter size at birth and weaning, viability rate at birth, hemoglobin and red blood cells, and plasma T3, T4, insulin, total proteins and albumin compared with control. Plasma estradiol 17-ß (pre-mating), progesterone (mid-pregnancy), and prolactin (day -7 postpartum) were significantly increased only by SeNPs (0.3, 0.4, and 0.5 mg/kg). All dietary supplements significantly reduced WBCs, cortisol, lipid profile, and improved liver and kidney functions. Immunoglobulins levels, antioxidants capacity were significantly increased, superoxide dismutase was increased by SeNPs (0.4 and 0.5 mg/kg), while malondialdehyde was reduced by 0.3, 0.4 and 0.5 SeNPs mg/kg. Sexual receptivity, pregnancy rate, viability rate at weaning, ovulation rate, and embryo quality were significantly increased by increasing SeNPs above 0.1 mg, while embryo yield was increased by >0.2 mg SeNPs/kg. A combination of SP and SeNPs, could be potentially used as a strong antioxidant to enhance heat regulation and doe rabbit reproduction via improving reproductive and metabolic hormones, antioxidant status and immunological parameters.

Evaluation of Facial Esthetics Following NAM Versus CAD/NAM in Infants With Bilateral Cleft Lip and Palate: A Randomized Clinical Trial.

OBJECTIVE: The aim is to compare the facial esthetics following nasoalveolar molding (NAM) versus computer-aided design NAM (CAD/NAM) in patients with bilateral cleft lip/palate (CLP). DESIGN: The trial is a randomized comparative trial with a 1:1 allocation ratio. PARTICIPANTS: Thirty infants with bilateral complete cleft lip and palate were recruited. INTERVENTIONS: Patients were randomized between NAM and CAD/NAM groups. The treatment steps described by Grayson were followed for the NAM group. In the CAD/NAM group, digitized maxillary models were made to create a series of modified virtual models, which were used to fabricate the molding plates using 3-dimensional printing technology. The nasal stents were then added to the intraoral plates following the Grayson method. The study lasted for 4 months. MAIN OUTCOMES: The assessment of the changes observed in the interlabial gap and nasolabial esthetics was done using standardized 2-dimensional photographs. The correlation between dental arch changes and extraoral facial esthetics was studied. RESULTS: Both modalities showed improvement in nasolabial esthetics before the lip surgery. No statistically significant difference was found between NAM and CAD/NAM groups in any of the assessed variables. CONCLUSIONS: Both interventions were effective in the management of infants with bilateral CLP.

Discovery of allosteric SHP2 inhibitors through ensemble-based consensus molecular docking, endpoint and absolute binding free energy calculations.

SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a cytoplasmic protein -tyrosine phosphatase encoded by the gene PTPN11. It plays a crucial role in regulating cell growth and differentiation. Specifically, SHP2 is an oncoprotein associated with developmental pathologies and several different cancer types, including gastric, leukemia and breast cancer and is of great therapeutic interest. Given these roles, current research efforts have focused on developing SHP2 inhibitors. Allosteric SHP2 inhibitors have been shown to be more selective and pharmacologically appealing compared to competitive catalytic inhibitors targeting SHP2. Nevertheless, there remains a need for novel allosteric inhibitor scaffolds targeting SHP2 to develop compounds with improved selectivity, cell permeability, and bioavailability. Towards this goal, this study applied various computational tools to screen over 6 million compounds against the allosteric site within SHP2. The top-ranked hits from our in-silico screening were validated using protein thermal shift and biolayer interferometry assays, revealing three potent compounds. Kinetic binding assays were employed to measure the binding affinities of the top-ranked compounds and demonstrated that they all bind to SHP2 with a nanomolar affinity. Hence the compounds and the computational workflow described herein provide an effective approach for identifying and designing a generation of improved allosteric inhibitors of SHP2.

Clinical Assessment of Cytokine Profiles and Haematological Parameters in Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study from Saudi Arabia.

BACKGROUND: Systemic lupus erythematosus (SLE)-related hematological disorders have different pathogenic mechanisms involving immune dysregulation as well as microangiopathy. The current study aimed to assess the relationship between pro- and anti-inflammatory cytokines and SLE-related hematological abnormalities for Saudi Patients. METHODS: The current cross-sectional study including 140 participants was performed at the Prince Mohammad bin Abdulaziz Hospital (PMAH), Riyadh, Saudi Arabia. Two blood samples were collected from each of the study participants for evaluation of the haematological indices including complete blood count (CBC), erythrocyte sedimentation rate (ESR), and cytokine profile (i.e., tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10)). Statistical analyses were performed using the Statistical Package of Social Sciences (SPSS) software, v25. RESULTS: Haematological abnormalities were documented in 63% of SLE patients, and anaemia was the highest at 52%. Haemoglobin levels were found to be significantly lower among SLE patients compared to the controls (p < 0.001). In the cytokine profiles, the levels of TNF-α (p < 0.001), IL-6 (p < 0.001), and IL-10 (p = 0.009) were significantly higher among SLE patients compared to the controls. A positive correlation was also identified between TNF-α, platelet count, red cell distribution width (RDW), and ESR. CONCLUSIONS: Haematological abnormalities were found to be the most common among SLE patients. Further, the correlation between cytokine profile and haematological indices indicates the influence of cytokines in the development of haematological abnormalities. Understanding hematological abnormalities and cytokines' role in the pathogenesis of these abnormalities may aid in the early diagnosis and development of more specific SLE disease therapies.

Prevalence of Fibromyalgia Syndrome in Taif City, Saudi Arabia.

Introduction Fibromyalgia syndrome (FMS) is a non-inflammatory, chronic disseminated musculoskeletal pain with unknown etiology. FMS patients suffer from generalized pain that markedly decreases their quality of life and productivity. Objective To investigate the prevalence of FMS and the correlation between people with positive screening criteria for FMS and their socio-demographic characteristics in Taif city. Methodology A cross-sectional study was performed in Taif city, Saudi Arabia, from June 2021 to August 2021. A structured self-estimated electronic questionnaire developed by Google Forms. The questionnaire depended on the 2010 American College of Rheumatology (ACR) criteria. Data analysis was performed by using SPSS, version 21.0 (IBM Corp., Armonk, NY). Result Out of 1015 participants, 77 participants (7.6%) were revealed to have FMS. The prevalence of FMS among females (9.3%) was significantly higher (p<0.001) than that among males (3.1%). In addition, participants aged 40 years old or more showed a significantly higher prevalence of FMS (p=0.003) compared to those aged less than 40 years old (11.7% versus 6.0%, respectively). In addition, occupational status was found to significantly affect FMS prevalence (p=0.040) as the highest prevalence was reported among employees (10.8%) and housewives (9.4%) compared to the unemployed (8.8%), students (5.0%), and retired participants (4.0%). On the other hand, participants' nationality was shown to have no significant effect on fibromyalgia prevalence (p=0.396). Conclusion Results show a slightly high prevalence rate of FMS in Saudi Arabia. Prevalence was seen greater in women, old age, and employed individuals. Poor knowledge of FMS was seen among the general Saudi population. Educational programs are needed to increase awareness of the disease.

Insights into the implication of obesity in hypogonadism among adolescent boys.

OBJECTIVES: This research aimed at uncovering the mechanisms behind obesity-related hypogonadism in adolescent boys and to investigate the association between anthropometric characteristics and testicular functions of these boys. METHODS: This study included 60 adolescent boys (12-18 years) with exogenous obesity (BMI≥95th percentile) and 30 age matched lean controls (BMI=15th-85th percentile). Full clinical examination, anthropometric measurements and pubertal assessment were performed. Laboratory investigations included hemoglobin, hematocrit, lipid panel, LH, FSH, free and total testosterone, inhibin B and estradiol. RESULTS: The results indicated the presence of positive family history of obesity in 85% of obese boys vs. 40% of the lean counterparts. Concerning SBP of obese boys, 7% were hypertensive (95th percentile), 25% were prehypertensive (between 90th and 95th percentiles) while, DBP findings showed that 33% are hypertensive and 33% are prehypertensive. Meanwhile, 13.3% of lean controls were prehypertensive. Anthropometric measurements and lipid profile values revealed a significant difference between obese and lean boys. Compared to obese boys the normal weight boys had higher levels of free testosterone (21.15 ± 2.90 pg/mL vs. 11.38 ± 3.96 pg/mL, p<0.001), total testosterone (10.59 ± 6.63 ng/dL vs. 3.23 ± 1.70 ng/dL, p<0.001), FSH (7.33 ± 3.75 mIU/mL vs. 5.63 ± 3.96 mIU/mL, p=0.026) and inhibin B (83.28 ± 27.66 pg/mL vs. 62.90 ± 17.85 pg/mL, p=0.001) and they registered lower level of estradiol (18.48 ± 7.33 pg/mL vs. 40.20 ± 7.91 pg/mL, p<0.001). In obese boys, BMI SDS significantly correlated with lipid profile and estradiol whereas, it showed significant negative correlation with LH, free and total testosterone and inhibin B. Penile length significantly correlated with LH while it revealed significant negative correlation with cholesterol. CONCLUSIONS: This study evidenced a close association between obesity and hypogonadism in adolescent boys which could be due to the increased estradiol level and decreased T/E2 ratio.

Assessment of the efficacy of thymol against Toxocara vitulorum in experimentally infected rats.

The effect of thymol and ivermectin on the development and embryonation of Toxocara vitulorum (T. vitulorum) eggs, as well as their migration in albino rats was investigated both in vitro and in vivo. A total of forty male albino rats were divided into four groups for an in vivo experiment. The first group was uninfected; the second group was infected but left untreated; the third group was infected and received thymol at a dose of 40 mg/kg; and the fourth group was infected and received ivermectin (0.2 mg/kg). In vitro, thymol inhibited the development of Toxocara larvae within the eggs. However, ivermectin, produced inconsistent results. The in vivo results indicated that the recovery rates of Toxocara larvae from the liver and lungs on day 7 post-infection were significantly lower in the thymol or ivermectin-treated groups than in the infected untreated control. Albumin levels were significantly increased in the thymol-treated group as compared to the positive control and ivermectin groups. Nitric oxide, IL-4, and IFN- levels in the serum of the thymol or ivermectin-treated groups were significantly lower than that of the positive control group. Histopathological examination demonstrated that thymol and ivermectin were effective in reducing larval load, reducing the number and size of granulomas in the absence of larvae, and improving tissue architecture. The current study concluded that thymol possessed anti-Toxocara activity in a rat model. Additionally, thymol possessed ovicidal properties and may be used as a disinfectant.

Recurrent Adipsic Hypernatremia in a Fully Independent Non-psychiatric Patient With Multiple Congenital Anomalies: A Case Report.

Osmoregulation is a fundamental process of homeostasis that maintains metabolic and biochemical reactions, thermoregulation, and fluid-electrolytes balance. Fluid-electrolytes imbalance leads to various clinical manifestations ranging from mild weakness to severe neurological dysfunction. Adipsic hypernatremia is an exceedingly rare life-threatening condition characterized by defective osmoregulatory mechanisms. It is more often reported in patients with severe untreated psychiatric disorders for unknown etiologies, but it may result from congenital or acquired hypothalamic lesions in the form of stroke, neoplastic infiltration, trauma, or infection. Herein we report an unusual case of isolated hypernatremia in a fully independent non-psychiatric 27-year-old diabetic male with spina bifida, repaired cleft palate, and mild caudal regression syndrome.

Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor Side-Chains.

Inhibition of DNA repair enzymes is an attractive target for increasing the efficacy of DNA damaging chemotherapies. The ERCC1-XPF heterodimer is a key endonuclease in numerous single and double strand break repair processes, and inhibition of the heterodimerization has previously been shown to sensitize cancer cells to DNA damage. In this work, the previously reported ERCC1-XPF inhibitor 4 was used as the starting point for an in silico study of further modifications of the piperazine side-chain. A selection of the best scoring hits from the in silico screen were synthesized using a late stage functionalization strategy which should allow for further iterations of this class of inhibitors to be readily synthesized. Of the synthesized compounds, compound 6 performed the best in the in vitro fluorescence based endonuclease assay. The success of compound 6 in inhibiting ERCC1-XPF endonuclease activity in vitro translated well to cell-based assays investigating the inhibition of nucleotide excision repair and disruption of heterodimerization. Subsequently compound 6 was shown to sensitize HCT-116 cancer cells to treatment with UVC, cyclophosphamide, and ionizing radiation. This work serves as an important step towards the synergistic use of DNA repair inhibitors with chemotherapeutic drugs.

Transoral Endoscopic Resection of Oropharyngeal Pedunculated Giant Fibrolipoma Using Harmonic Scalpel: A Case Report.

Lipoma is the most common soft tissue benign tumor in the body. It can occur in the head and neck area as well. Fibrolipoma is a variant of lipoma that contains fibrous tissue. Fibrolipomas of the head and neck are relatively rare, and their presentation depends largely on their size and location; some slowly growing tumors might go unnoticed until they reach significant size and become symptomatic. Here, we report a case of 64-year-old male who presented with large pedunculated oropharyngeal fibrolipoma that originated from the posterior oropharyngeal wall and extended downward into the postcricoid area and cervical esophagus. It was excised transorally using rigid endoscope, and ACE Harmonic scalpel was utilized to excise this 16.7 cm long mass. The postoperative pain was minimal, the surgical site showed complete healing, and oral diet was resumed easily in 5 days.

Hypothyroidism and the risk of coronary artery disease in Saudi patients.

BACKGROUND: Hypothyroidism has been described in the literature as a risk factor for coronary artery disease (CAD). An association between thyroid-stimulating hormone (TSH) levels and CAD has been confirmed. In Saudi Arabia, there has been no study on the relationship between hypothyroidism and CAD. Therefore, the aim of this study was to investigate the prevalence and risk factors of CAD in patients with hypothyroidism. MATERIALS AND METHODS: This cross-sectional study conducted at King Abdulaziz Medical City in Riyadh (KAMC-R), included 412 adult hypothyroid patients who were followed up between 2013 and 2018. The data was collected on demographics, CAD-related risk factors, and hypothyroidism. In addition, relevant laboratory tests, including thyroid function tests, lipid profile, and hemoglobin A1c, were collected. SPSS version 28.0 was used for data analysis. Categorical data were presented as frequencies and percentages, while mean and standard deviations were computed for the numerical data. Student's t-test used to test statistical significance for numerical variables and Chi- square test was performed to test the differences between categorical variables. Multivariate binary logistic regression was used to determine the effects of gender, BMI, family history (CAD), smoking, hypertension, and TSH on CAD. RESULTS: Of the 412 hypothyroid patients, 21.8% were diagnosed with CAD, with more prevalence in men (44.15%) than in women (15.4%). About 46% had hypertension, 2.2% were smokers, and 2.4% had family history of CAD. Older age was significantly associated with a higher prevalence of CAD compared to younger age groups. The mean of TSH was significantly higher in CAD patients than non-CAD patients before and at diagnosis with CAD (P < 0.001). For every 1mIU/L increase in the TSH level, the odds of developing CAD increased significantly by 4.8% (P = 0.014). The odds ratios for other CAD risk factors were 3.13 for males, 8.1 for smoking, 2.48 for hypertension, and 9.9 for family history of CAD (P < 0.05). CONCLUSION: The prevalence of CAD in hypothyroid patients was higher than in the general population. TSH level was significantly associated with CAD. Male gender, older age, smoking, hypertension, family history of CAD, and high TSH level increased the likelihood of developing CAD.

Efficacy and safety of monopolar versus bipolar radial head arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Radial head replacement is the main line of treating complex unstable elbow injuries. Radial head prostheses are either monopolar or bipolar. The difference between both designs in patients' clinical outcomes and postoperative complications is not yet clear. So, a systematic review and meta-analysis was conducted to evaluate the efficacy and safety of monopolar vs. bipolar implants. MATERIALS AND METHODS: PubMed, EMBASE, Cochrane, and Scopus were searched to identify studies comparing monopolar and bipolar implants. Data on clinical outcomes, postoperative complications, revision, and removal rates were extracted. RESULTS: Nine studies met our inclusion criteria, with a total of 591 patients (365 monopolar and 226 bipolar). Both prostheses achieved similar ranges of motion; Mayo Elbow Performance Score; Disabilities of the Arm, Shoulder, and Hand score; and visual analog scale for pain. Incidence of postoperative complications was also similar between both designs. Revision and removal rates were 24%, 8% and 29%, 14% for monopolar and bipolar implants, respectively, but no statistically significant difference could be detected. CONCLUSIONS: No significant difference was found between monopolar and bipolar radial head prostheses in terms of efficacy and safety. Therefore, high-quality randomized controlled trials are required to determine the superiority of one design over the other.