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International Journal of Neonatal... Nov 2020Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase...
Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.
PubMed: 33202836
DOI: 10.3390/ijns6040089 -
Genes & Diseases Jul 2023Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of...
Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.
PubMed: 37397523
DOI: 10.1016/j.gendis.2022.12.005 -
World Journal of Urology Feb 2022Percutaneous nephrolithotomy (PCNL) is the treatment of choice for patients with large stones. The risk of acute kidney injury (AKI) has not been reported in the Western...
INTRODUCTION AND OBJECTIVE
Percutaneous nephrolithotomy (PCNL) is the treatment of choice for patients with large stones. The risk of acute kidney injury (AKI) has not been reported in the Western world. Our objective was to assess the frequency of AKI in patients undergoing PCNL and to identify independent predictors of AKI.
METHODS
A retrospective review of PCNL cases performed between January 2014 and June 2019 was reformed. Demographic, laboratory, and intraoperative date were obtained. Perioperative AKI was defined as (1) Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 micromol/L) within 48 h, or (2) increase in serum creatinine to ≥ 1.5 times baseline. Multivariable logistic regression analysis was performed to determine the factors influencing AKI. A p value of 0.05 was considered significant.
RESULTS
A total of 566 patients were included. Mean age was 58 ± 14.4 years. The frequency of AKI was 4.4% (n = 25). The risk factors for AKI after PCNL were having a baseline creatinine > 1.54 mg/dl (p = 0.03, odds ratio [OR] = 2.66, confidence interval [CI] = 1.07-6.6), and a preoperative hemoglobin of less than 10.6 g/dL (p = 0.02, odds ratio [OR] = 2.47, confidence interval [CI] = 1.09-5.5). Patients without AKI had a median hospitalization of 2 days, while those with an AKI were hospitalized for a median of 3 days, and this difference was statistically significant (p < 0.001).
CONCLUSIONS
Perioperative AKI occurs in 4.4% of patients undergoing PCNL. Preoperative hemoglobin and serum creatinine can identify those at increased risk, in whom it may be important to avoid nephrotoxic agents.
Topics: Acute Kidney Injury; Adult; Aged; Creatinine; Humans; Incidence; Middle Aged; Nephrolithotomy, Percutaneous; Odds Ratio; Postoperative Complications; Retrospective Studies; Risk Factors
PubMed: 34806118
DOI: 10.1007/s00345-021-03874-4 -
Bioorganic & Medicinal Chemistry Letters Sep 2022Both poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) are important antitumor targets and have attracted extensive attention. In this work, a total...
Both poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) are important antitumor targets and have attracted extensive attention. In this work, a total of fourteen PARP-1/HDAC dual targeting inhibitors were designed and synthesized using either benzopyrazole or benzimidazole as core structures. Two leading compounds 1-8-6 and 1-8-7 were proven to be dual targeting inhibitors of PARP-1 and HDAC6, and showed high antiproliferative activities against six human cancer cell lines with IC values in micromole range. Moreover, compounds 1-8-6 and 1-8-7 could impair tumor cell proliferation in 48 h and 72 h with much higher potency than co-treatment of Olaparib and Tubastatin A. 1-8-6 displayed remarkable anti-migration and anti-angiogenesis activities. Meanwhile, western blot experiment result showed that 1-8-6 was able to heighten expression level of acetylated α-tubulin with marginal effects to acetylated histones H3 and H4. Finally, docking simulation work showed that 1-8-6 could fit into the active sites of PARP-1 and HDAC6. All results indicated that 1-8-6 is a promising candidate for further preclinical studies.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Structure-Activity Relationship
PubMed: 35643262
DOI: 10.1016/j.bmcl.2022.128821 -
BJC Reports 2024Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is...
BACKGROUND/OBJECTIVES
Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.
SUBJECTS/METHODS
In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays.
RESULTS
The primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4.
CONCLUSIONS
Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.
PubMed: 38312352
DOI: 10.1038/s44276-023-00035-5 -
Natural Product Research Apr 2021Sacroflavonoside, a new derivative of diphenylethene, was isolated from , which have been found to possess the inhibitory effect on the proliferation of gastric...
Sacroflavonoside, a new derivative of diphenylethene, was isolated from , which have been found to possess the inhibitory effect on the proliferation of gastric carcinoma cells (MKN-45) in our previous studies. With anisaldehyde (SM-A) as starting material, the sacroflavonoside was synthesized by nucleophilic addition, electrophilic substitution and dehydration cyclization. The structure of sacroflavonoside was established by 1 D (H NMR and C NMR) and 2 D-NMR (HSQC and HMBC) spectral analysis. The antitumor activity and potential mechanism against MKN-45 cells of sacroflavonoside were evaluated . The results showed that sacroflavonoside could significantly induce MKN-45 cells apoptosis and autophagy by increasing the expression of Bax, Caspase-3, Beclin1 and LC3-II proteins and decreasing the expression of Bcl-2 protein at low micromole level. This investigation provided a valuable lead structure for the development of antitumor drugs.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Artemisia; Autophagy; Beclin-1; Benzaldehydes; Caspase 3; Cell Line, Tumor; Cyclization; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Proto-Oncogene Proteins c-bcl-2; Stomach Neoplasms
PubMed: 31359788
DOI: 10.1080/14786419.2019.1645660 -
Cureus Jul 2019Bariatric surgery is recognized as a highly effective therapy for obesity but it does carry a risk of short term and long term complications since it results in a...
Bariatric surgery is recognized as a highly effective therapy for obesity but it does carry a risk of short term and long term complications since it results in a permanent alteration of the patient's anatomy. We present a case of 45-year-old female presented with a macular rash on extremities and facial rash from a rehabilitation center after having been discharged a month earlier from a revision surgery on her gastric bypass for anastomotic bleeding. She progressively became lethargic with Magnetic Resonance Imaging (MRI) of the brain showed symmetrically restricted diffusion concerning for hypoxic injury. Her ammonia levels were at 142 micromoles per liter (mmol/L) at the initial check which worsened to 432 mmol/L over a few days, despite treatment. Laboratory investigation later revealed her to be deficient in zinc along with many essential and nonessential amino acids. Supplemental nutrition was initiated, specifically fortifying her parenteral feeds with the essential amino acid combinations that were found deficient on testing. This lead to a slow but progressive improvement in encephalopathy. This case highlights the importance of understanding the short and long term complications of bariatric surgery. Although neurological complications are rare with peripheral neuropathy being the most common one, hyperammonemic encephalopathy is a very severe complication, with incompletely understood mechanisms and predispositions, frequently resulting in failure of recognition and subsequent delays in intervention.
PubMed: 31511810
DOI: 10.7759/cureus.5098 -
Molecular and Cellular Biology Apr 2022Protein arginine methyltransferase (PRMT) enzymes catalyze posttranslational modifications of target proteins and are often upregulated in human cancers. In this study,...
Protein arginine methyltransferase (PRMT) enzymes catalyze posttranslational modifications of target proteins and are often upregulated in human cancers. In this study, we purified two chemical compounds from seeds of based on their ability to inhibit the enzymatic activity of PRMT5. These two compounds were identified as Pheophorbide a (PPBa) and Pheophorbide b (PPBb), two breakdown products of chlorophyll. PPBa and PPBb inhibited the enzymatic activity of both Type I and Type II PRMTs with IC values at sub micromole concentrations, inhibited the arginine methylation of histones in cells, and suppressed proliferation of prostate cancer cells. Molecular docking results predicted that PPBa binds to an allosteric site in the PRMT5 structure with a high affinity (ΔG = -9.0 kcal/mol) via hydrogen bond, ionic, and π-π stacking interactions with amino acid residues in PRMT5. Another group of natural compounds referred to as protoporphyrins and sharing structural similarity with pheophorbide also inhibited the PRMT enzymatic activity. This study is the first report on the PRMT-inhibitory activity of the tetrapyrrole macrocycles and provides useful information regarding the application of these compounds as natural therapeutic reagents for cancer prevention and treatment.
Topics: Arginine; Histones; Humans; Male; Methylation; Molecular Docking Simulation; Protein-Arginine N-Methyltransferases
PubMed: 35311588
DOI: 10.1128/mcb.00523-21 -
Plants (Basel, Switzerland) Jun 2024Alpha-amylases are crucial hydrolase enzymes which have been widely used in food, feed, fermentation, and pharmaceutical industries. Methods for low-cost production of...
Alpha-amylases are crucial hydrolase enzymes which have been widely used in food, feed, fermentation, and pharmaceutical industries. Methods for low-cost production of α-amylases are highly desirable. Soybean seed, functioning as a bioreactor, offers an excellent platform for the mass production of recombinant proteins for its ability to synthesize substantial quantities of proteins. In this study, we generated and characterized transgenic soybeans expressing the α-amylase AmyS from . The α-amylase expression cassettes were constructed for seed specific expression by utilizing the promoters of three different soybean storage peptides and transformed into soybean via -mediated transformation. The event with the highest amylase activity reached 601 U/mg of seed flour (one unit is defined as the amount of enzyme that generates 1 micromole reducing ends per min from starch at 65 °C in pH 5.5 sodium acetate buffer). The optimum pH, optimum temperature, and the enzymatic kinetics of the soybean expressed enzyme are similar to that of the expressed enzyme. However, the soybean expressed α-amylase is glycosylated, exhibiting enhanced thermostability and storage stability. Soybean AmyS retains over 80% activity after 100 min at 75 °C, and the transgenic seeds exhibit no significant activity loss after one year of storage at room temperature. The accumulated AmyS in the transgenic seeds represents approximately 15% of the total seed protein, or about 4% of the dry seed weight. The specific activity of the transgenic soybean seed flour is comparable to many commercial α-amylase enzyme products in current markets, suggesting that the soybean flour may be directly used for various applications without the need for extraction and purification.
PubMed: 38891347
DOI: 10.3390/plants13111539