Bioisosteric modification of Linezolid identified the potential M. tuberculosis protein synthesis inhibitors to overcome the myelosuppression and serotonergic toxicity associated with Linezolid in the treatment of the multi-drug resistance tuberculosis (MDR-TB).

Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against M. tuberculosis and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (3071, 7549 and 9660) as less toxic potential modulators of Mtb EthR protein. Compounds 3071, 7549 and 9660 were having the significant docking score of -12.696 Kcal/mol, -12.681 Kcal/mol and -15.293 Kcal/mol towards the Mtb EthR protein with less MAO-A and B affinity [compound 3071: MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound 7549: MAO A (> -2.00 Kcal/mol) and MAO B (> -2.00 Kcal/mol) and compound 9660: MAO A (> -5.678 Kcal/mol) and MAO B (> -6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid.Communicated by Ramaswamy H. Sarma.

Evaluating antibiotic regimens for streptococcal toxic shock syndrome in children.

INTRODUCTION: Streptococcal toxic shock syndrome (STSS) is a severe consequence of infections from Streptococcus pyogenes. The early identification and timely intervention with appropriate anti-infective agents are pivotal for managing pediatric STSS. This study evaluates the effectiveness of various treatment regimens for STSS in children. METHODS: Clinical data of children with STSS resulting from ß-hemolytic streptococcal infections in two hospitals were retrospectively analyzed from January 2009 to April 2023. Additionally, literature from the China National Knowledge Infrastructure on pediatric STSS was examined. Antimicrobial treatments were categorized into four groups based on their compositions, with an additional categorization for adjunct therapeutic drugs. RESULTS: Of 32 confirmed STSS cases, all displayed sensitivity to ampicillin, ß-lactam antibiotics, and vancomycin, but resistance to clindamycin, erythromycin, and tetracycline. From the literature, 23 studies with 50 cases were extracted, leading to a total of 82 patients for evaluation. The efficacy rates varied significantly among the four treatment groups. Notably, the standard penicillin-containing group exhibited the highest efficacy (86.4%), while the group with macrolides/unused antibiotics registered a 0% efficacy rate. The other two groups demonstrated efficacy rates of 32.1% and 42.3%. CONCLUSION: For pediatric STSS, Streptococcus pyogenes shows notable sensitivity to ampicillin. Implementing timely ß-lactam antibiotics, specifically penicillin, in conjunction with clindamycin and intravenous immunoglobulins enhances the treatment success rate.

Systematic Review of Hospital Treatment Outcomes for Naturally Acquired and Bioterrorism-Related Anthrax, 1880-2018.

BACKGROUND: Bacillus anthracis can cause anthrax and is a potential bioterrorism agent. The 2014 Centers for Disease Control and Prevention recommendations for medical countermeasures against anthrax were based on in vitro data and expert opinion. However, a century of previously uncompiled observational human data that often includes treatment and outcomes is available in the literature for analysis. METHODS: We reviewed treatment outcomes for patients hospitalized with anthrax. We stratified patients by meningitis status, route of infection, and systemic criteria, then analyzed survival by treatment type, including antimicrobials, antitoxin/antiserum, and steroids. Using logistic regression, we calculated odds ratios and 95% confidence intervals to compare survival between treatments. We also calculated hospital length of stay. Finally, we evaluated antimicrobial postexposure prophylaxis (PEPAbx) using data from a 1970 Russian-language article. RESULTS: We identified 965 anthrax patients reported from 1880 through 2018. After exclusions, 605 remained: 430 adults, 145 children, and 30 missing age. Survival was low for untreated patients and meningitis patients, regardless of treatment. Most patients with localized cutaneous or nonmeningitis systemic anthrax survived with 1 or more antimicrobials; patients with inhalation anthrax without meningitis fared better with at least 2. Bactericidal antimicrobials were effective for systemic anthrax; addition of a protein synthesis inhibitor(s) (PSI) to a bactericidal antimicrobial(s) did not improve survival. Likewise, addition of antitoxin/antiserum to antimicrobials did not improve survival. Mannitol improved survival for meningitis patients, but steroids did not. PEPAbx reduced risk of anthrax following exposure to B. anthracis. CONCLUSIONS: Combination therapy appeared to be superior to monotherapy for inhalation anthrax without meningitis. For anthrax meningitis, neither monotherapy nor combination therapy were particularly effective; however, numbers were small. For localized cutaneous anthrax, monotherapy was sufficient. For B. anthracis exposures, PEPAbx was effective.

Sarecycline: A Narrow-Spectrum Antibiotic.

Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis.

BACKGROUND: Multiple myeloma (MM) remains an incurable cancer despite advances in therapy. Therefore, the search for new targets is still essential to uncover potential treatment strategies. Metabolic changes, induced by the hypoxic bone marrow, contribute to both MM cell survival and drug resistance. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1 and PYCR2) are two mitochondrial enzymes that facilitate the last step in the glutamine-to-proline conversion. Overexpression of PYCR1 is involved in progression of several cancers, however, its' role in hematological cancers is unknown. In this study, we investigated whether PYCR affects MM viability, proliferation and response to bortezomib. METHODS: Correlation of PYCR1/2 with overall survival was investigated in the MMRF CoMMpass trial (653 patients). OPM-2 and RPMI-8226 MM cell lines were used to perform in vitro experiments. RPMI-8226 cells were supplemented with 13C-glutamine for 48 h in both normoxia and hypoxia (< 1% O2, by chamber) to perform a tracer study. PYCR1 was inhibited by siRNA or the small molecule inhibitor pargyline. Apoptosis was measured using Annexin V and 7-AAD staining, viability by CellTiterGlo assay and proliferation by BrdU incorporation. Differential protein expression was evaluated using Western Blot. The SUnSET method was used to measure protein synthesis. All in vitro experiments were performed in hypoxic conditions. RESULTS: We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis. Finally, combination therapy of pargyline with bortezomib reduced viability in CD138+ MM cells and reduced tumor burden in the murine 5TGM1 model compared to single agents. CONCLUSIONS: This study identifies PYCR1 as a novel target in bortezomib-based combination therapies for MM.

Tetracycline ameliorates silica-induced pulmonary inflammation and fibrosis via inhibition of caspase-1.

BACKGROUND: Inhalation of dust containing silica particles is associated with severe pulmonary inflammation and lung injury leading to chronic silicosis including fibrotic remodeling of the lung. Silicosis represents a major global health problem causing more than 45.000 deaths per year. The inflammasome-caspase-1 pathway contributes to the development of silica-induced inflammation and fibrosis via IL-1ß and IL-18 production. Recent studies indicate that tetracycline can be used to treat inflammatory diseases mediated by IL-1ß and IL-18. Therefore, we hypothesized that tetracycline reduces silica-induced lung injury and lung fibrosis resulting from chronic silicosis via limiting IL-1ß and IL-18 driven inflammation. METHODS: To investigate whether tetracycline is a therapeutic option to block inflammasome-caspase-1 driven inflammation in silicosis, we incubated macrophages with silica alone or combined with tetracycline. The in vivo effect of tetracycline was determined after intratracheal administration of silica into the mouse lung. RESULTS: Tetracycline selectively blocks IL-1ß production and pyroptotic cell death via inhibition of caspase-1 in macrophages exposed to silica particles. Consistent, treatment of silica-instilled mice with tetracycline significantly reduced pulmonary caspase-1 activation as well as IL-1ß and IL-18 production, thereby ameliorating pulmonary inflammation and lung injury. Furthermore, prolonged tetracycline administration in a model of chronic silicosis reduced lung damage and fibrotic remodeling. CONCLUSIONS: These findings suggest that tetracycline inhibits caspase-1-dependent production of IL-1ß in response to silica in vitro and in vivo. The results were consistent with tetracycline reducing silica-induced pulmonary inflammation and chronic silicosis in terms of lung injury and fibrosis. Thus, tetracycline could be effective in the treatment of patients with silicosis as well as other diseases involving silicotic inflammation.

The naturally occurring flavonoid nobiletin reverses methotrexate resistance via inhibition of P-glycoprotein synthesis.

Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp-mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp-induced drug efflux.

Suppressive Effects of Anisomycin on the Proliferation of B16 Mouse Melanoma Cells In Vitro.

BACKGROUND: Anisomycin, a potential anticancer therapeutic drug, exerts an antitumor effect on melanoma cells at a lower concentration than that required for other cancer cells. However, the molecular mechanisms remain unclear. MATERIALS AND METHODS: The sensitivity to and cytotoxicity of anisomycin, as well as the effects of anisomycin on glucose metabolism and relative mRNA expression of senescence- and cancer-associated genes, were studied using B16 mouse melanoma cells. RESULTS: The viability of anisomycin-treated cells decreased in a concentration-dependent manner, and the growth of cell spheroids was suppressed by 50 nM anisomycin. Glucose metabolism was reduced by anisomycin treatment, and the mRNA expression of genes responsible for growth inhibition, such as p21, p53 and Txnip was upregulated. CONCLUSION: The results suggest that anisomycin may be a promising future anticancer drug that is effective at low concentrations against melanoma by reducing glucose metabolism, causing cell senescence-like phenomena.

eIF3a R803K mutation mediates chemotherapy resistance by inducing cellular senescence in small cell lung cancer.

Drug resistance in small cell lung cancer (SCLC) significantly affects the efficacy of chemotherapy treatment. However, due to the lack of tumor tissue samples, especially serial tumor samples during chemotherapy, the mechanism of chemotherapy resistance has not been fully studied. Circulating tumor DNA, which can be obtained in a noninvasive manner, can complement tumor sampling approaches for research in this field. We identified an SCLC patient with acquired drug resistance from 52 SCLC patients for whom follow-up data were available. By comparing somatic mutations in circulating tumor DNA before and after chemotherapy, for the first time, we found that the somatic mutation eIF3A R803K may be related to acquired chemotherapy resistance. Then, the association between the eIF3A R803K mutation and chemotherapy resistance was confirmed by samples from 254 lung cancer patients receiving chemotherapy. We found that the eIF3a R803K mutation weakened the proliferation ability of tumor cells but increased their resistance to chemotherapy. Further studies revealed that the eIF3A R803K mutation promotes cellular senescence. In addition, fisetin showed a synergistic effect with chemotherapy in eIF3A R803K mutant cells. These results suggest that the eIF3A R803K somatic mutation has the potential to predict chemotherapy resistance in SCLC. Moreover, the eIF3A R803K mutation promotes chemotherapy resistance by inducing senescence. Furthermore, a senolytic drug, fisetin, can reverse chemotherapy resistance mediated by the eIF3A R803K mutation.

Feline ocular toxoplasmosis: seroprevalence, diagnosis and treatment outcome of 60 clinical cases.

Toxoplasmosis is one of the most important protozoa zoonotic diseases worldwide. The present study describes the clinical, seroprevalence findings with ocular toxoplasmosis and the outcome of medicinal treatment of these cats. This study was carried out on 105 cats with various ocular signs, no historical evidence of ocular trauma or drug/vaccine exposure for at least 3 months prior to admission, and without clinical or laboratory evidence of other systemic diseases. Complete case history, physical and ophthalmic examinations were carried out. The seroprevalence of Toxoplasma gondii antibodies was determined using the Toxoplasma Ab Rapid Test and Enzyme Linked Immunosorbent Assay. Out of 105 examined cats with ocular lesions, 60 cats representing 57.14% were seropositive to T. gondii. Out of these 60 cats, 15 cats (25%) had bilateral ocular abnormalities, 25 cats (41.67%) had right-sided ocular disease, and 20 cats (33.33%) had left-sided ocular disease. There were 38 cats (63.33%) with anterior uveitis, 12 cats (20%) with posterior segment involvement, 5 cats (8.33%) with anterior uveitis and anterior chamber abnormalities, 3 cats (5%) with corneal abnormalities and 2 cats (3.34%) with anterior uveitis with concurrent corneal involvement. There was a significant difference in the index values of IgM and IgG between seropositive and seronegative cats with T. gondii antibodies (p⟨0.05). There was no significant difference between the different ages, genders and breeds of cats with seroprevalence of T. gondii antibodies as well as between the age and total number of cats with seropositive and seronegative T. gondii. Out of 60 treated cats, 28 cats (46.7%), 25 cats (41.7%) and 7 cats (11.6%) showed complete, partial and poor response to treatment, respectively. In conclusion, cats showing ocular signs without obvious etiology should be examined serologically for toxoplasmosis and the seropositive cats should be treated with both specific topical and systemic treatments.

Vulval acne: a case series describing clinical features and management.

Intermittent inflammation of the vulval pilosebaceous units is common and usually self-limiting, but some patients experience recurrent and more troublesome symptoms. There is a scarcity of information on this problem. We describe the clinical and histological features in these patients and the response to treatment. A retrospective, observational study of 16 patients with this phenomenon of recurrent, protracted folliculocentric inflammation of the vulval pilosebaceous unit was performed. Details on the clinical features, histology and response to treatment were collected. Mean age at presentation was 32 years (range 21-45). All patients reported recurrent painful papules and pustules on the labia majora and labia minora. Nine patients reported a cyclical pattern to the development of lesions, with premenstrual exacerbation being most common. Histological examination of these lesions showed a folliculocentric microabscess formation surrounded by an acute and chronic inflammatory cell infiltrate, with a focal foreign-body granulomatous reaction. All our patients responded well to tetracycline, antiandrogenic or retinoid therapy. We propose the term 'vulval acne' for this condition and propose a stepwise approach to its management. We hope to highlight this as a common but underreported entity.

Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy.

PURPOSE: The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen-specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine. EXPERIMENTAL DESIGN: We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis. RESULTS: Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival. CONCLUSIONS: Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.

The efficacy and safety of a homoharringtonine-based protocol for children with acute myeloid leukemia: A retrospective study in China.

The standard chemotherapy for acute myeloid leukemia (AML) is usually composed of anthracyclines and cytarabine. We previously reported that homoharringtonine (HHT) was incorporated into regimens for pediatric AML with acceptable efficacy and tolerable toxicity. We treated newly diagnosed AML patients aged 0-18 years on the AML-SCMC-2009 protocol. A total of 102 de novo newly diagnosed AML patients aged 0-18 years were enrolled. All patients were treated with ten courses of chemotherapy including double induction, high dose cytarabine consolidation, and maintenance. The cumulative dose of HHT was 165 mg/m2 and the daunorubicin dose was 120 mg/m2. Complete remission (CR), overall survival (OS) rate, event free survival (EFS) rate, adverse effect response and prognosis factors were retrospectively evaluated to investigate the long-term outcome and safety of this protocol. Eighty-two patients (80.4%) achieved complete remission with the first induction. The 5-year overall survival and event-free survival rates were 65.0% (SE, 4.9%) and 53.3% (SE, 5.2%), respectively. A first induction failure, age older than 2 years, and BCR-ABL translocation were associated with a significantly worse outcome (p < 0.05). No significant drug-related cardiac toxicity was observed. AML-SCMC-2009 protocol which use HHT as backbone drug is efficacious and tolerated. HHT could partially replace anthracycline to be an effective option for childhood AML.

A Quick Guide to Small-Molecule Inhibitors of Eukaryotic Protein Synthesis.

Eukaryotic ribosome and cap-dependent translation are attractive targets in the antitumor, antiviral, anti-inflammatory, and antiparasitic therapies. Currently, a broad array of small-molecule drugs is known that specifically inhibit protein synthesis in eukaryotic cells. Many of them are well-studied ribosome-targeting antibiotics that block translocation, the peptidyl transferase center or the polypeptide exit tunnel, modulate the binding of translation machinery components to the ribosome, and induce miscoding, premature termination or stop codon readthrough. Such inhibitors are widely used as anticancer, anthelmintic and antifungal agents in medicine, as well as fungicides in agriculture. Chemicals that affect the accuracy of stop codon recognition are promising drugs for the nonsense suppression therapy of hereditary diseases and restoration of tumor suppressor function in cancer cells. Other compounds inhibit aminoacyl-tRNA synthetases, translation factors, and components of translation-associated signaling pathways, including mTOR kinase. Some of them have antidepressant, immunosuppressive and geroprotective properties. Translation inhibitors are also used in research for gene expression analysis by ribosome profiling, as well as in cell culture techniques. In this article, we review well-studied and less known inhibitors of eukaryotic protein synthesis (with the exception of mitochondrial and plastid translation) classified by their targets and briefly describe the action mechanisms of these compounds. We also present a continuously updated database (http://eupsic.belozersky.msu.ru) that currently contains information on 370 inhibitors of eukaryotic protein synthesis.

Exploring Drug Treatment Patterns Based on the Action of Drug and Multilayer Network Model.

Some drugs can be used to treat multiple diseases, suggesting potential patterns in drug treatment. Determination of drug treatment patterns can improve our understanding of the mechanisms of drug action, enabling drug repurposing. A drug can be associated with a multilayer tissue-specific protein-protein interaction (TSPPI) network for the diseases it is used to treat. Proteins usually interact with other proteins to achieve functions that cause diseases. Hence, studying drug treatment patterns is similar to studying common module structures in multilayer TSPPI networks. Therefore, we propose a network-based model to study the treatment patterns of drugs. The method was designated SDTP (studying drug treatment pattern) and was based on drug effects and a multilayer network model. To demonstrate the application of the SDTP method, we focused on analysis of trichostatin A (TSA) in leukemia, breast cancer, and prostate cancer. We constructed a TSPPI multilayer network and obtained candidate drug-target modules from the network. Gene ontology analysis provided insights into the significance of the drug-target modules and co-expression networks. Finally, two modules were obtained as potential treatment patterns for TSA. Through analysis of the significance, composition, and functions of the selected drug-target modules, we validated the feasibility and rationality of our proposed SDTP method for identifying drug treatment patterns. In summary, our novel approach used a multilayer network model to overcome the shortcomings of single-layer networks and combined the network with information on drug activity. Based on the discovered drug treatment patterns, we can predict the potential diseases that the drug can treat. That is, if a disease-related protein module has a similar structure, then the drug is likely to be a potential drug for the treatment of the disease.

Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma.

Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. SIGNIFICANCE: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.

A comparison of endolymphatic shunt surgery and intratympanic gentamicin for meniere's disease.

OBJECTIVE: To report audiovestibular outcomes following endolymphatic shunt surgery (ELS) and intratympanic gentamicin injections (ITG) in patients with Meniere's disease (MD). STUDY DESIGN: Retrospective matched cohort study METHODS: Patients with MD refractory to medical management between 2004 and 2017 were reviewed: 44 patients underwent ELS and had outcomes available, while 27 patients underwent ITG and had outcomes available. Mean follow-up durations for the ELS and ITG groups were 39.1 and 43.3 months, respectively. Twenty-six patients from the ELS group and 24 patients from the ITG group were then included in a pretreatment hearing- and age-matched analysis. Main outcome measures were successful control of vertigo, pure-tone average (PTA; 0.5, 1, 2 and 4 kHz), word recognition score (WRS), and treatment complications. RESULTS: A matched analysis showed vertigo control rates of 73.1% in the ELS group and 66.8% in the ITG group, which were not significantly different (P = .760). The change in PTA following treatment was statistically similar between the ELS group (6.2 dB) and ITG group (4.6 dB) (P = .521), while the change in WRS for the ELS group (+3.9 %) was significantly more favorable than the ITG group (-13.6 %) (P = .046). Chronic post-treatment unsteadiness was reported in 25.0% of the ITG group and was not encountered in the ELS group (P = .009). CONCLUSION: ELS provided successful vertigo control at least as well as ITG with a lower incidence of audiovestibular complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2455-2460, 2020.

Therapeutic Potential of Medicinal Plant Proteins: Present Status and Future Perspectives.

Biologically active molecules obtained from plant sources, mostly including secondary metabolites, have been considered to be of immense value with respect to the treatment of various human diseases. However, some inevitable limitations associated with these secondary metabolites like high cytotoxicity, low bioavailability, poor absorption, low abundance, improper metabolism, etc., have forced the scientific community to explore medicinal plants for alternate biologically active molecules. In this context, therapeutically active proteins/peptides from medicinal plants have been promoted as a promising therapeutic intervention for various human diseases. A large number of proteins isolated from the medicinal plants have been shown to exhibit anti-microbial, anti-oxidant, anti-HIV, anticancerous, ribosome-inactivating and neuro-modulatory activities. Moreover, with advanced technological developments in the medicinal plant research, medicinal plant proteins such as Bowman-Birk protease inhibitor and Mistletoe Lectin-I are presently under clinical trials against prostate cancer, oral carcinomas and malignant melanoma. Despite these developments and proteins being potential drug candidates, to date, not a single systematic review article has documented the therapeutical potential of the available biologically active medicinal plant proteome. The present article was therefore designed to describe the current status of the therapeutically active medicinal plant proteins/peptides vis-à-vis their potential as future protein-based drugs for various human diseases. Future insights in this direction have also been highlighted.

Administration of Protein Synthesis Inhibitor before Reminder Reverses Amnesia Induced by Memory Reconsolidation Impairment with 5-HT Receptors Antagonist.

Administration of 5-HT receptor antagonist to snails trained in conditioned food aversion prior to reminding of the conditioning stimulus caused amnesia. At the early period of amnesia (day 3), injections of protein synthesis inhibitor cycloheximide without reminder or reminder alone were ineffective. At the same time, injections of the inhibitor combined with reminder led to memory recovery; this effect in most animals persisted for at least 10 days. In the rest snails, aversive responses to presentations of the conditioning stimulus persisted for 2 days. Cycloheximide injection and reminder in 10 days after induction of amnesia did not affect its development or caused a transient memory recovery (2 days). We hypothesized that amnesia is an active process unfolding in time. One of mechanism of this process is reminder-induced and protein synthesis-depended reactivation of amnesia. Inhibitor of protein synthesis disturbed this reactivation and led to recovery of the initial memory of conditioned food aversion.