Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 668
Filter
1.
Article in English | MEDLINE | ID: mdl-38904470

ABSTRACT

ABSTRACT: Odontomes are the most common benign odontogenic tumors of the jaw which are usually slow-growing and non-aggressive. They are generally asymptomatic and diagnosed during routine radiographic investigations and are mostly associated with tooth eruption disturbances. The present case series report covers seven cases of odontomes discussing on clinical, radiographic, and histopathologic features (ground section and decalcification) along with a brief review of the literature.

2.
J Int AIDS Soc ; 27(6): e26315, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38924347

ABSTRACT

INTRODUCTION: As access to effective antiretroviral therapy (ART) has improved globally, tobacco-related illnesses, including cardiovascular disease, cancer and chronic respiratory conditions, account for a growing proportion of deaths among people with HIV (PWH). We estimated the impact of tobacco smoking and smoking cessation on life expectancy among PWH in South Africa. METHODS: In a microsimulation model, we simulated 18 cohorts of PWH with virologic suppression, each homogenous by sex, initial age (35y/45y/55y) and smoking status (current/former/never). Input parameters were from data sources published between 2008 and 2022. We used South African data to estimate age-stratified mortality hazard ratios: 1.2-2.3 (females)/1.1-1.9 (males) for people with current versus never smoking status; and 1.0-1.3 (females)/1.0-1.5 (males) for people with former versus never smoking status, depending on age at cessation. We assumed smoking status remains unchanged during the simulation; people who formerly smoked quit at model start. Simulated PWH face a monthly probability of disengagement from care and virologic non-suppression. In sensitivity analysis, we varied smoking-associated and HIV-associated mortality risks. Additionally, we estimated the total life-years gained if a proportion of all virologically suppressed PWH stopped smoking. RESULTS: Forty-five-year-old females/males with HIV with virologic suppression who smoke lose 5.3/3.7 life-years compared to PWH who never smoke. Smoking cessation at age 45y adds 3.4/2.4 life-years. Simulated PWH who continue smoking lose more life-years from smoking than from HIV (females, 5.3 vs. 3.0 life-years; males, 3.7 vs. 2.6 life-years). The impact of smoking and smoking cessation increase as smoking-associated mortality risks increase and HIV-associated mortality risks, including disengagement from care, decrease. Model results are most sensitive to the smoking-associated mortality hazard ratio; varying this parameter results in 1.0-5.1 life-years gained from cessation at age 45y. If 10-25% of virologically suppressed PWH aged 30-59y in South Africa stopped smoking now, 190,000-460,000 life-years would be gained. CONCLUSIONS: Among virologically suppressed PWH in South Africa, tobacco smoking decreases life expectancy more than HIV. Integrating tobacco cessation interventions into HIV care, as endorsed by the World Health Organization, could substantially improve life expectancy.


Subject(s)
HIV Infections , Life Expectancy , Smoking Cessation , Tobacco Smoking , Humans , Male , Female , HIV Infections/drug therapy , HIV Infections/mortality , South Africa/epidemiology , Adult , Smoking Cessation/statistics & numerical data , Middle Aged , Tobacco Smoking/epidemiology , Computer Simulation
3.
Abdom Radiol (NY) ; 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38937338

ABSTRACT

A wide spectrum of benign and malignant primary mesenchymal tumors and tumor-like lesions of the spleen has been recently included under the umbrella term 'stroma-derived' neoplasms and tumor-like lesions. These include dendritic cell neoplasms such as follicular dendritic cell sarcoma, EBV-positive inflammatory follicular dendritic cell sarcoma, and fibroblastic reticular cell tumor; smooth muscle and myofibroblastic lesions such as inflammatory pseudotumor, EBV-associated smooth muscle tumor and undifferentiated pleomorphic sarcoma as well as a diverse spectrum of vascular and vascular-stromal tumors and tumor-like lesions. While some tumor and tumor-like lesions are unique to the spleen, others may also occur in diverse extra-splenic viscera. These tumors and tumor-like lesions demonstrate characteristic histopathology, immunocytochemistry and biological behavior. While cross-sectional imaging studies allow detection, staging and limited characterization of these splenic lesions, histopathological confirmation permits optimal management and surveillance strategies.

4.
Abdom Radiol (NY) ; 49(5): 1716-1733, 2024 05.
Article in English | MEDLINE | ID: mdl-38691132

ABSTRACT

There is a diverse group of non-gastrointestinal stromal tumor (GIST), mesenchymal neoplasms of the gastrointestinal (GI) tract that demonstrate characteristic pathology and histogenesis as well as variable imaging findings and biological behavior. Recent advancements in tumor genetics have unveiled specific abnormalities associated with certain tumors, influencing their molecular pathogenesis, biology, response to treatment, and prognosis. Notably, giant fibrovascular polyps of the esophagus, identified through MDM2 gene amplifications, are now classified as liposarcomas. Some tumors exhibit distinctive patterns of disease distribution. Glomus tumors and plexiform fibromyxomas exhibit a pronounced affinity for the gastric antrum. In contrast, smooth muscle tumors within the GI tract are predominantly found in the esophagus and colorectum, surpassing the incidence of GISTs in these locations. Surgical resection suffices for symptomatic benign tumors; multimodality treatment may be necessary for frank sarcomas. This article aims to elucidate the cross-sectional imaging findings associated with a wide spectrum of these tumors, providing insights that align with their histopathological features.


Subject(s)
Gastrointestinal Neoplasms , Humans , Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Diagnostic Imaging/methods
5.
J Clin Oncol ; : JCO2300699, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701382

ABSTRACT

PURPOSE: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses. METHODS: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes. RESULTS: In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC. CONCLUSION: Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.

6.
Article in English | MEDLINE | ID: mdl-38722777

ABSTRACT

OBJECTIVE: To perform image quality comparison between deep learning-based multiband diffusion-weighted sequence (DL-mb-DWI), accelerated multiband diffusion-weighted sequence (accelerated mb-DWI), and conventional multiband diffusion-weighted sequence (conventional mb-DWI) in patients undergoing clinical liver magnetic resonance imaging (MRI). METHODS: Fifty consecutive patients who underwent clinical MRI of the liver at a 1.5-T scanner, between September 1, 2021, and January 31, 2022, were included in this study. Three radiologists independently reviewed images using a 5-point Likert scale for artifacts and image quality factors, in addition to assessing the presence of liver lesions and lesion conspicuity. RESULTS: DL-mb-DWI acquisition time was 65.0 ± 2.4 seconds, significantly (P < 0.001) shorter than conventional mb-DWI (147.5 ± 19.2 seconds) and accelerated mb-DWI (94.3 ± 1.8 seconds). DL-mb-DWI received significantly higher scores than conventional mb-DWI for conspicuity of the left lobe (P < 0.001), sharpness of intrahepatic vessel margin (P < 0.001), sharpness of the pancreatic contour (P < 0.001), in-plane motion artifact (P = 0.002), and overall image quality (P = 0.005) by reader 2. DL-mb-DWI received significantly higher scores for conspicuity of the left lobe (P = 0.006), sharpness of the pancreatic contour (P = 0.020), and in-plane motion artifact (P = 0.042) by reader 3. DL-mb-DWI received significantly higher scores for strength of fat suppression (P = 0.004) and sharpness of the pancreatic contour (P = 0.038) by reader 1. The remaining quality parameters did not reach statistical significance for reader 1. CONCLUSIONS: Novel diffusion-weighted MRI sequence with deep learning-based image reconstruction demonstrated significantly decreased acquisition times compared with conventional and accelerated mb-DWI sequences, while maintaining or improving image quality for routine abdominal MRI. DL-mb-DWI offers a potential alternative to conventional mb-DWI in routine clinical liver MRI.

7.
ChemMedChem ; : e202400251, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38746978

ABSTRACT

Hydrogen sulfide (H2S) is considered the third member of the gasotransmitter family, along with nitric oxide (NO) and carbon monoxide (CO). Besides its role in physiological and pathophysiological conditions, the promising therapeutic potential of this small-molecule makes it advantageous for various pharmaceutical applications. The endogenous production of H2S at a lower concentration is crucial in maintaining redox balance and cellular homeostasis, and the dysregulation leads to various disease states. In the event of H2S deficiency, the exogenous donation of H2S could help maintain the optimal cellular concentration of H2S and cellular homeostasis. Over the last several years, researchers have developed numerous small-molecule non-fluorogenic organosulfur compounds as H2S donors and investigated their pharmacological potentials. However, reports on stimuli-responsive turn-on fluorogenic donors of H2S have appeared recently. Interestingly, the fluorogenic H2S donors offer additional advantages with the non-invasive real-time monitoring of the H2S release utilizing the simultaneous turn-on fluorogenic processes. The review summarizes the recent developments in turn-on fluorogenic donors of H2S and the potential biological applications that have developed over the years.

8.
Biodegradation ; 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38687420

ABSTRACT

Single-use facial masks which are predominantly made out of polypropylene is being used and littered in large quantities during post COVID-19 situation. Extensive researches on bioremediation of plastic pollution on soil led to the identification of numerous plastic degrading microorganisms. These organisms assimilate plastic polymers as their carbon source for synthesizing energy. Pseudomonas fluorescens (PF) is one among such microorganism which is being identified to biodegrade plastic polymers in controlled environment. The natural biodegradation of facial mask in soil-like fraction collected from municipal waste management site, bioaugmentation of the degradation process with Pseudomonas fluorescens, biostimulation of the soil with carbonless nutritional supplements and combined bioaugmentation with biostimulation process were studied in the present work. The study has been conducted both in controlled and in natural condition for a period of 12 months. The efficiency of the degradation was verified through FTIR analyses using carbonyl index, bond energy change, Loss in ignition (LOI) measurement along with CHNS analyses of residual substances. The analysis of results reported that carbonyl index (in terms of transmittance) was reduced to 46% of the control batch through the inclusion of PF in natural condition. The bioaugmented batch maintained in natural condition showed 33% reduction of LOI with respect to the control batch. The unburnt carbon content of the residual matter obtained from the furnace were analysed using CHNS analyser and indicated the lowest carbon content in the same bioaugmented batch. In this study, an attempt is made to verify the feasibility of enhancing biodegradation of single-use facial mask by bioaugmentation of soil-like fraction available in solid waste management park with Pseudomonas fluorescens under natural condition. CHNS and FTIR analysis assures the biodegradation of plastic waste in the soil-like fraction using Pseudomonas fluorescens under both controlled and natural environmental condition.

9.
J Mater Chem B ; 12(17): 4248-4261, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38602387

ABSTRACT

Prolonged use of very commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with undesired side effects, including gastrointestinal ulcers due to the non-selective inhibition of cyclooxygenases. We describe the development of an inflammatory-stimuli-responsive turn-on fluorogenic theranostic prodrug DCF-HS for adjuvant drug delivery. Upon activation by reactive oxygen species (ROS), the prodrug releases diclofenac DCF (active drug) and the NIR fluorophore DCI-NH2 along with carbonyl sulfide (COS). The second activation of COS by the enzyme carbonic anhydrase (CA) generates hydrogen sulfide (H2S). The prodrug was conveniently synthesized using multi-step organic synthesis. The UV-Vis and fluorescence studies revealed the selective reactivity of DCF-HS towards ROS such as H2O2 in the aqueous phase and the desired uncaging of the drug DCF with turn-on NIR fluorescent reporter under physiological conditions. Furthermore, the release of fluorophore DCI-NH2 and drug DCF was confirmed using the reverse phase HPLC method. Compatibility of prodrug activation was studied next in the cellular medium. The prodrug DCF-HS was non-toxic in a representative cancer cell line (HeLa) and a macrophage cell line (RAW 264.7) up to 100 µM concentration, indicating its biocompatibility. The intracellular ROS-mediated activation of the prodrug with the release of NIR dye DCI-NH2 and H2S was investigated in HeLa cells using the H2S-selective probe WSP2. The anti-inflammatory activity of the active drug DCF from the prodrug DCF-HS was studied in the lipopolysaccharide (LPS)-induced macrophage cell line and compared to that of the parent drug DCF using western blot analysis and it was found that the active drug resulted in pronounced inhibition of COX-2 in a dose-dependent manner. Finally, the anti-inflammatory potential of the prodrug and the turn-on fluorescence were validated in the inflammation-induced Wister rat models.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Diclofenac , Hydrogen Sulfide , Prodrugs , Prodrugs/pharmacology , Prodrugs/chemistry , Prodrugs/chemical synthesis , Hydrogen Sulfide/metabolism , Animals , Humans , Diclofenac/pharmacology , HeLa Cells , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Rats , Theranostic Nanomedicine , Inflammation/drug therapy , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Fluorescent Dyes/chemical synthesis , Mice , RAW 264.7 Cells , Drug Delivery Systems , Edema/drug therapy , Edema/chemically induced
10.
Musculoskelet Sci Pract ; 71: 102949, 2024 06.
Article in English | MEDLINE | ID: mdl-38583363

ABSTRACT

BACKGROUND: The Dynamic Neuromuscular Stabilization (DNS) diaphragm test and intra-abdominal pressure regulation test (IAPRT) are qualitative clinical tests that assess postural stability provided by the diaphragm. OBJECTIVE: Evaluate the inter-rater reliability of the diaphragm test and IAPRT between an experienced and novice DNS clinician among individuals with non-specific low back pain (LBP) and neck pain. METHODS: Forty-five participants with non-specific LBP and/or neck pain were assessed by an experienced and novice DNS physiotherapist in the diaphragm test and IAPRT, and scored on a visual analog scale (VAS) according to five different criteria. RESULTS: Moderate reliability was noted when assessing LBP and neck pain patients in the diaphragm test and IAPRT (p < 0.001). Moderate reliability also existed when assessing only LBP (p < 0.001) or neck pain (p = 0.002, p = 0.009) independently. Patients with lower pain (NPRS score of 5 or < ) demonstrated lower intra-class correlation coefficients, yet still moderate reliability in the diaphragm test (p = 0.004) and IAPRT (p = 0.001). Patients with higher pain (NPRS score of 6 or > ) demonstrated greater intra-class correlation coefficients, with the diaphragm test resulting in good reliability (p < 0.001). CONCLUSIONS: The diaphragm test and IAPRT demonstrate moderate reliability between an experienced and novice DNS clinician when evaluating LBP and neck pain patients, with a greater degree of reliability noted in patients suffering from higher reported pain.


Subject(s)
Diaphragm , Low Back Pain , Neck Pain , Humans , Female , Low Back Pain/physiopathology , Low Back Pain/diagnosis , Male , Adult , Reproducibility of Results , Diaphragm/physiopathology , Neck Pain/physiopathology , Neck Pain/diagnosis , Middle Aged , Pain Measurement/methods , Postural Balance/physiology , Observer Variation
11.
J Org Chem ; 89(8): 5825-5832, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38597506

ABSTRACT

Herein, we describe our efforts culminating in the total syntheses of discoipyrroles A, B, and C in 6, 6, and 7 steps respectively with excellent overall yield. Total syntheses of these unique natural products have been accomplished involving microwave-mediated Paal-Knorr pyrrole synthesis, Pd-catalyzed carbonylative transformation, and MoOPH (Vedejs reagent) oxidation as key reactions to construct the 1,2,3,5-tetrasubstituted pyrrole and oxidative cyclization of highly substituted pyrrole as key steps.

12.
Int J Surg Case Rep ; 117: 109558, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38518469

ABSTRACT

INTRODUCTION AND IMPORTANCE: Acute colonic pseudo-obstruction (ACPO) is an uncommon phenomenon that is especially rare in young patients and can result in bowl ischemia and perforation if left untreated. Furthermore, pneumoperitoneum is almost always a concerning imaging finding and in the context of recent colonic resection may be a sign of anastomotic leakage. CASE PRESENTATION: We describe a case of a young female patient with postpartum ACPO who subsequently underwent a hemicolectomy with colorectal anastomosis. The patient's hospital course was complicated by massive postoperative pneumoperitoneum that resulted in resection of the anastomosis and creation of an end colostomy. However, despite this measure, there was recurrent pneumoperitoneum on cross-sectional imaging 36 h later. This was treated non-operatively and the remainder of their hospital course was uneventful. CLINICAL DISCUSSION: A potential etiology for ACPO during pregnancy may be due to compression of parasympathetic plexus nerves by the gravid uterus. Idiopathic pneumoperitoneum has been documented on a number of occasions, though this is generally in older patients. It can present with signs of peritonitis or can be asymptomatic. Simultaneous pneumothorax and pneumoperitoneum is rare and may be due to the transmission of air from the peritoneum to the mediastinum and thorax. The pneumoperitoneum itself may be due the air leakage through the significantly distended colon into the peritoneum. CONCLUSION: The combination of ACPO following pregnancy and associated pneumothorax, pneumomediastinum, and recurrent pneumoperitoneum suggest a communicating defect between the thoracic, mediastinal, and peritoneal cavities. Furthermore, the possibility of underlying colonic dysmotility should be considered prior to the restoration of large bowel continuity.

13.
Sci Adv ; 10(9): eadk3074, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38416824

ABSTRACT

Cancer cells program fibroblasts into cancer associated fibroblasts (CAFs) in a two-step manner. First, cancer cells secrete exosomes to program quiescent fibroblasts into activated CAFs. Second, cancer cells maintain the CAF phenotype via activation of signal transduction pathways. We rationalized that inhibiting this two-step process can normalize CAFs into quiescent fibroblasts and augment the efficacy of immunotherapy. We show that cancer cell-targeted nanoliposomes that inhibit sequential steps of exosome biogenesis and release from lung cancer cells block the differentiation of lung fibroblasts into CAFs. In parallel, we demonstrate that CAF-targeted nanoliposomes that block two distinct nodes in fibroblast growth factor receptor (FGFR)-Wnt/ß-catenin signaling pathway can reverse activate CAFs into quiescent fibroblasts. Co-administration of both nanoliposomes significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 in immunocompetent lung cancer-bearing mice. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/ß-catenin signaling constitutes a promising approach to augment immunotherapy.


Subject(s)
Exosomes , Lung Neoplasms , Animals , Mice , Exosomes/metabolism , Cell Proliferation/genetics , Fibroblasts/metabolism , Lung Neoplasms/genetics , Phenotype , Immunotherapy , Cell Line, Tumor
14.
Org Lett ; 26(6): 1138-1142, 2024 02 16.
Article in English | MEDLINE | ID: mdl-38306609

ABSTRACT

Engineering biosynthetic pathways to ribosomally synthesized and post-translationally modified peptides (RiPPs) offers several advantages for both in vivo and in vitro applications. Here we probe the ability of peptide cyclases to generate trimacrocycle microviridin analogs with non-native cross-links. The results demonstrate that diverse chemistries are tolerated by macrocyclases in the ATP-grasp family and allow for the construction of unique cyclic peptide architectures that retain protease inhibition activity. In addition, cocomplex structures of analogs bound to a model protease were determined, illustrating how changes in functional groups maintain peptide conformation and target binding.


Subject(s)
Peptides, Cyclic , Peptides , Peptides, Cyclic/chemistry , Peptides/chemistry , Peptide Hydrolases
15.
AIDS ; 38(8): 1186-1197, 2024 07 01.
Article in English | MEDLINE | ID: mdl-38329107

ABSTRACT

OBJECTIVE: Almost 400 000 people with HIV (PWH) in the United States are over age 55 years and at risk for age-associated dementias (AAD), including Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). We projected the cumulative incidence and mortality associated with AAD among PWH at least 60 years in the United States compared with the general population. DESIGN/METHODS: Integrating the CEPAC and AgeD-Pol models, we simulated two cohorts of 60-year-old male and female individuals: PWH, and the general US population. We estimated AAD incidence and AAD-associated mortality rates. Projected outcomes included AAD cumulative incidence, life expectancy, and quality-adjusted life-years (QALYs). We performed sensitivity and scenario analyses on AAD-specific (e.g. incidence) and HIV-specific (e.g. disengagement from HIV care) parameters, as well as premature aging among PWH. RESULTS: We projected that 22.1%/16.3% of 60-year-old male individuals/female individuals with HIV would develop AAD by 80 years compared with 15.9%/13.3% of male individuals/female individuals in the general population. Accounting for age-associated and dementia-associated quality of life, 60-year-old PWH would have a lower life expectancy (QALYs): 17.4 years (14.1 QALYs) and 16.8 years (13.4 QALYs) for male and female individuals, respectively, compared with the general population [male individuals, 21.7 years (18.4 QALYs); female individuals, 24.7 years (20.2 QALYs)]. AAD cumulative incidence was most sensitive to non-HIV-related mortality, engagement in HIV care, and AAD incidence rates. CONCLUSION: Projected estimates of AAD-associated morbidity, mortality, and quality of life can inform decision-makers and health systems planning as the population of PWH ages. Improved AAD prevention, treatment, and supportive care planning are critical for people aging with HIV.


Subject(s)
HIV Infections , Humans , Male , Female , Middle Aged , United States/epidemiology , HIV Infections/epidemiology , HIV Infections/complications , Incidence , Aged , Aged, 80 and over , Dementia/epidemiology , Life Expectancy , Quality-Adjusted Life Years , Aging
16.
Microbiol Spectr ; 12(4): e0358623, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38391232

ABSTRACT

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.


Subject(s)
Mpox (monkeypox) , Orthopoxvirus , Smallpox , Variola virus , Animals , Mice , Humans , Nucleosides/therapeutic use , Smallpox/drug therapy , Smallpox/prevention & control , Disease Models, Animal
17.
Chem Commun (Camb) ; 60(25): 3397-3400, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38404238

ABSTRACT

Biothiol-activatable prodrug RK-296 was designed for the delivery of potent anti-cancer agent NBDHEX with concomitant turn-on near infrared (NIR) fluorescence. NBDHEX exhibits anti-cancer activity by selectively inhibiting glutathione-S-transferase pi (GSTP1), which is overexpressed in cancer cells and responsible for the inactivation of chemotherapeutic drugs. The sustained release of NBDHEX from the prodrug would be useful for ameliorating the off-target side-effects of NBDHEX.


Subject(s)
Biotin , Prodrugs , Fluorescence , Prodrugs/pharmacology , Prodrugs/therapeutic use , Cell Line, Tumor , Oxadiazoles/pharmacology
18.
J Mol Model ; 30(2): 57, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38300376

ABSTRACT

CONTEXT: Organic semiconductors (OSCs) have attracted a great deal of interest in recent days. There are various types of OSCs, among which small molecules have various inherent benefits. Further research is needed to advance this new kind of material because the field is still developing, and the current focus is on creating small molecules that exist naturally for OSCs. OSCs with nonlinear optical (NLO) characteristics offer a significant advantage over others. Thus, this study theoretically investigates naturally occurring anthraquinones such as chrysophanol and rhein as potential OSCs, as well as their NLO properties. The calculated properties include the ionization potential (IP), electron affinity (EA), and bandgap (Eg). The FMO energy levels together with the Eg, IP (8.17-8.53 eV), and EA (1.87-2.44 eV) suggest the semiconductor nature of the studied compounds. The calculated values of reorganization energy (λ) and transfer integrals (V) suggest the p-type character of both molecules. Rhein has the lowest λh (0.19 eV) and Eg (3.28 eV) and the highest Vh, predominantly because of its better p-type character. The polarizability increases due to the presence of an electron-withdrawing substituent, leading to better NLO performance for Rhein, which is supported by its lower LUMO and Eg values. METHODS: The studied molecules were optimized with the DFT/B3LYP-GD3/6-31+G(d,p) method using Gaussian 16 software. The crystal structure was simulated with Materials Studio 7.0, and the V values were calculated with the ADF package. The CDD and DOS plots were obtained with the Multiwfn 3.8 program.

19.
Heliyon ; 10(1): e24023, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38230235

ABSTRACT

This study investigated the top three musculoskeletal pains (MSP) among Hispanic construction workers in Texas and the relationship between sleep hours, age, and MSPs on worker productivity. The study recruited 228 participants from 28 small construction companies and surveyed them on their occupation, age, sleep hours, MSP, and the impact of pain on productivity. The results indicated that Foot pain was the most common among these workers, followed by Back pain and others. Additionally, the study found that the Foot was the most common body part reported with MSP among roofers, drywall installers, laborers, and helpers. The study conducted a three-factor ANOVA test to analyze if there were any significant differences in productivity based on age, number of MSPs, and sleep hours. The study found that MSPs and sleep hours significantly impacted productivity. However, there was no significant effect of age. The results also showed that the number of MSPs significantly impacted productivity, with an increase in MSPs leading to a more severe impact on productivity. Additionally, those who slept less than 6 h per day had a more severe impact on productivity than those who slept more. The study suggests that targeted interventions to improve musculoskeletal health and productivity in this population are needed and highlights the importance of considering Hispanic construction workers' specific needs when implementing safety measures and addressing pain management in the workplace.

20.
Heliyon ; 10(1): e23712, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38192868

ABSTRACT

A compact high bandwidth ratio (BDR) super wide band flower slotted micro strip patch antenna (SWB-FSMPA) for super wide band (SWB) applications is presented. The SWB-FSMPA is constructed on a FR-4 substrate having a size of 16 × 22 mm2. The SWB-FSMPA incorporates a 50 Ω tapered micro strip line and a rectangular beveled defected ground structure (RB-DGS). This design enables a simulation bandwidth from 3.78 to 109.86 GHz, allowing for coverage of various wireless applications such as WiMAX (3.3-3.6 GHz), 5G (3.3-3.7 GHz), WLAN (5.15-5.825 GHz), UWB (3.1-10.6 GHz), Ku- (12-18 GHz), K- (18-27 GHz), Ka- (27-40 GHz), V- (40-75 GHz), and W- (75-110 GHz) millimeter wave bands. The SWB-FSMPA antenna exhibits a gain that varies within the range of 3.22-7.23 dBi and a peak efficiency of 93.3 %. The SWB-FSMPA possesses a bandwidth ratio (BR) of 29.1:1, a BDR of 5284 in the frequency domain, a minimal group delay (GD) fluctuation of <0.48 ns, and a linear phase in the time domain, making it well-suited for SWB applications.

SELECTION OF CITATIONS
SEARCH DETAIL
...