Experiments and Molecular Simulations to Study the Effect of Surface-Active Compounds in Mixtures of Model Oils on CO2 Corrosion during Intermittent Oil-Water Wetting.

Intermittent oil-water wetting can have a significant effect on the internal corrosion of steel pipelines. This paper presents a combined experimental and molecular modeling study of several influential factors on the surface properties and corrosion behavior of mild steel in CO2 environments. The influence of different model oils (LVT-200 and Aromatic-200) and select surface-active compounds (myristic acid, cyclohexane butyric acid, and oleic acid) on the corrosion behavior of carbon steel during intermittent oil-water wetting was determined by measuring the corrosion rate after intermittent wetting cycles. The interfacial tension measurements were performed to study the incorporation of the oil phase along with surface-active molecules in the protective layer formed on the specimen surface. Results showed that the interfacial tension for an aromatic oil-water interface is lower than that for an aliphatic oil-water interface. To understand this result, molecular dynamics simulations of oil-water interfaces were performed in the presence of surface-active molecules and different oils to analyze the structure of the layer formed at the interface. The simulations supported the hypothesis that aromatic molecules are less structured at the interface, which results in the incorporation of more water molecules into the protective layer formed at the steel surface, causing a higher corrosion rate. On the other hand, the simulations revealed that myristic acid in an aliphatic oil forms a well-aligned structure at the interface, devoid of any water molecules. This is in agreement with the hypothesis that the linear molecular structure of myristic acid favors the alignment of molecules at an aliphatic oil-water interface, resulting in a lower interfacial tension and more effective corrosion mitigation as compared to the other two nonlinear compounds tested. It is concluded that an important factor controlling the corrosion behavior is the molecular structure of the oil-water interface, which is adopted by the steel surface layer through the Langmuir-Blodgett process.

A Clinical Review and Experience of Splenic Trauma in North India: A Retrospective Observational Study.

INTRODUCTION: The spleen is one of the frequently injured solid organs in abdominal blunt trauma. The standard of care is nonoperative nowadays depending on the hemodynamic stability (World Society of Emergency Surgery (WSES) grade I-III) of the patient due to advancements in treating modalities. Operative interventions are required in hemodynamically unstable patients or failure of nonoperative management. The study was planned to find the clinical spectrum of abdominal blunt trauma, specifically those having splenic trauma, and their subsequent management in an institution. METHODS: This is a retrospective observational study. All included patients with blunt abdominal injuries were treated in a level 1 trauma center between July 2021 and December 2022. Data regarding demographic profile, blood transfusion, pre- and postoperative findings, and management including the period of hospital stay, morbidity, and mortality were collected and analyzed. RESULTS: One hundred sixty-four patients were analyzed, of which 142 were males and 22 were females. The commonest mechanism of injury was motor vehicle collision, followed by falls. Grade III splenic injury was the most common injury, while the predominantly associated injury was rib fracture. The patients were managed preferably through nonoperative management, followed by angioembolization and operative management. The commonest postoperative complication was pneumonia. CONCLUSIONS: Nonoperative management of splenic trauma has evolved as the standard of care replacing operative management in order to sustain its immune function, thereby preventing overwhelming post-splenectomy infection.

Comparing Three-Dimensional Digitally Enabled Intraoperative OCT With Conventional Microscope-Integrated OCT in Vitreoretinal Surgery: A Post Hoc Analysis of the Discover Study.

BACKGROUND AND OBJECTIVE: This study compared the surgeon experience between conventional microscope-integrated intraoperative optical coherence tomography (iOCT) and digitally enabled microscope-integrated iOCT in vitreoretinal surgery. PATIENTS AND METHODS: This is a post hoc case-control analysis of the DISCOVER study. Conventional microscope-integrated iOCT (Rescan 700, Zeiss) was compared with digitally enabled iOCT (Artevo 800, Zeiss). Compared variables included surgical field-based visualization (ie, ocular heads-up display in the conventional group; three-dimensional screen-based visualization in the digital iOCT group) and non-surgical field-based visualization (ie, review on the external two-dimensional monitor). RESULTS: A total of 200 patients were included. Surgical field-based visualization of iOCT was significantly higher in the digitally enabled group (P < 0.0001). Required endoillumination level was significantly lower in the digital iOCT group (P < 0.0001). Surgeons reported "significant" back discomfort and headache more frequently when using conventional iOCT (P = 0.003 and P = 0.001, respectively). CONCLUSIONS: Digitally enabled iOCT resulted in greater surgical visualization efficiency, appeared to require a lower illumination level, and may provide advantages for ergonomic-related discomfort. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Characterization of pentosan polysulfate patients for development of an alert and screening system for ophthalmic monitoring.

OBJECTIVE: Pentosan polysulfate (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, NJ) is a U.S. Food and Drug Administration-approved oral medication for interstitial cystitis. Numerous reports have been published detailing retinal toxicity with the use of PPS. Studies characterizing this condition are primarily retrospective, and consequently, alert and screening systems need to be developed to actively screen for this disease. The goal of this study was to characterize ophthalmic monitoring trends of a PPS-using patient sample to construct an alert and screening system for monitoring this condition. METHODS: A single-institution retrospective chart review was conducted between January 2005 and November 2020 to characterize PPS use. An electronic medical record (EMR) alert was constructed to trigger based on new PPS prescriptions and renewals offering ophthalmology referral. RESULTS: A total of 1407 PPS users over 15 years was available for characterization, with 1220 (86.7%) being female, the average duration of exposure being 71.2 ± 62.6 months, and the average medication cumulative exposure being 669.7 ± 569.2 g. A total of 151 patients (10.7%) had a recorded visit with an ophthalmologist, with 71 patients (5.0%) having optical coherence tomography imaging. The EMR alert fired for 88 patients over 1 year, with 34 patients (38.6%) either already being screened by an ophthalmologist or having been referred for screening. CONCLUSIONS: An EMR support tool can improve referral rates of PPS maculopathy screening with an ophthalmologist and may serve as an efficient method for longitudinal screening of this condition with the added benefit of informing pentosan polysulfate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.

Short-Term Outcomes of Faricimab in Patients with Neovascular Age-Related Macular Degeneration on Prior Anti-VEGF Therapy.

PURPOSE: A subset of patients with neovascular age-related macular degeneration (nAMD) experience treatment burden and suboptimal response with anti-VEGF therapy. The aim of this study was to investigate the effect of switching to a novel, bispecific agent, faricimab, in patients with nAMD currently treated with anti-VEGF. DESIGN: Retrospective, noncomparative cohort study. SUBJECTS: Patients with nAMD previously treated with anti-VEGF and switched to intravitreal faricimab injection (IFI) at the Cleveland Clinic's Cole Eye Institute. METHODS: Switching and administration schedule of IFI was at the discretion of the clinician. Visual acuity (VA) and macular OCT parameters, including central subfield thickness (CST), maximum pigment epithelial detachment (PED) height, and presence of subretinal (SRF) or intraretinal fluid (IRF), were assessed at baseline (day of first IFI) and after each IFI. MAIN OUTCOME MEASURES: Central subfield thickness and presence of IRF or SRF after ≥ 3 IFIs. RESULTS: One hundred twenty-six eyes of 106 patients were included in the analysis with a mean follow-up time of 24.3 ± 5.2 weeks. Before switching to IFI, patients received a mean of either aflibercept (20.0 ± 8.4, mean ± standard deviation), bevacizumab (7 ± 8.9), ranibizumab (1.9 ± 8.5), or brolucizumab (0.3 ± 1.6) injections. The most common agent used before switching to IFI was aflibercept (n = 110, 87%), and the mean treatment interval with any anti-VEGF was 5.6 ± 1.6 weeks before switching. Central subfield thickness was reduced from baseline after the first IFI (266.8 ± 64.7 vs. 249.8 ± 58.6 µm, P = 0.02) and persisted over the 3 IFIs (P = 0.01). Pigment epithelial detachment height was reduced after the third IFI (249.6 ± 179.0 vs. 206.9 ± 130.0 µm, P = 0.01). The mean VA (62.9 vs. 62.7 approximate ETDRS letters, P = 0.42) and interval between injections (6.3 vs. 5.7 weeks, P = 0.16) was similar after the third IFI compared with baseline. Eleven (8.7%) eyes were switched back to their previous anti-VEGF, including 2 (1.6%) eyes from 1 patient with intraocular inflammation requiring cessation of IFI. There were no other adverse events from switching. CONCLUSIONS: Switching to faricimab resulted in a reduction in mean CST (-11.6 µm, P = 0.01) and PED height (-44.2 µm, P = 0.01) after 3 injections, with stable VA and at a similar treatment interval to prior anti-VEGF therapy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Response to Acthar Gel in sarcoidosis uveitis: A prospective open label study.

PURPOSE: To investigate the response to Acthar Gel® in patients with moderate to severe sarcoidosis uveitis. METHODS: This is a prospective open-label study that enrolled patients with moderate to severe sarcoidosis uveitis to receive 80 units daily of Acthar Gel for ten days followed by maintenance treatment with 80 units twice weekly. The primary outcome was the proportion of patients meeting at least one of the following variables 1) improved visual acuity, 2) resolution of intraocular inflammation, 3) ability to taper ocular or oral steroids by at least 50% or 4) reduction of cystoid macular edema, with no worsening of any single measure and no need for additional sarcoidosis therapies at 24 weeks. RESULTS: A total of nine patients were enrolled in the study. Four patients completed the full 24-week course of Acthar Gel, and three of these met the primary endpoint. Among the five patients who did not complete the 24-week course of treatment, four discontinued the treatment due to worsening ocular inflammation. One patient discontinued treatment due to severe adverse effects. The most common adverse effects were fluid retention (77%), insomnia (44%), hypertension (44%) and hyperglycemia (44%). CONCLUSIONS: We observed a clinical response to Acthar Gel in some patients with moderate to severe sarcoidosis uveitis, but a substantial proportion either failed to respond or did not tolerate the therapy. These observations may serve as preliminary data for controlled trials of Acthar Gel, but they do not support its role prior to failure of other agents.

Multimodal Imaging Study of Patients With Vitamin A Deficiency Retinopathy.

OBJECTIVES: To describe multimodal imaging findings of vitamin A deficiency retinopathy. METHODS: A retrospective study of patients with serum retinol < 0.3 mg/L. Fundus color photos, spectral domain-optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were reviewed and, when available, electrophysiological tests were analyzed. RESULTS: Forty-five eyes (63.9 ± 15.7 years) were included. Ultra-widefield fundus photography showed drusen-like deposits (53.3%) and macular retinal pigment epithelium (RPE) mottling (40%). The deposits were hypoautofluorescent, and a perifoveal hyperautofluorescent ring was present in 8.9%. By SD-OCT, the ellipsoid zone had an irregular appearance (100%) and conical deposits anterior to the RPE (33.3%). Electroretinogram (ERG) (66.7%) showed a decrease in b-wave in the scotopic registers, and microperimetry (4.4%) showed decreased foveal sensitivity. After vitamin A supplementation, SD-OCT and FAF showed resolution of all findings. Forty percent of eyes had restoration of the scotopic registers in ERG and improved macular sensitivity by microperimetry (4.4%). CONCLUSIONS: Vitamin A deficiency causes a mild cone dysfunction in addition to the more severe absent rod response. [Ophthalmic Surg Lasers Imaging Retina 2023;54:330-336.].

Icariin ameliorates oxidative stress-induced inflammation, apoptosis, and heart failure in isoproterenol-challenged Wistar rats.

Objectives: Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days. Materials and Methods: Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. Results: A significant decline in hemodynamics and an anti-oxidant collapse were found in ISO-intoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal. Conclusion: Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection.

Vitreoretinal lymphoma with central nervous system involvement in a patient with sarcoidosis: a case report.

PURPOSE: To describe a case of primary vitreoretinal lymphoma with central nervous system involvement in a patient with sarcoidosis. METHODS: Single, retrospective chart review. PATIENT: A 59-year-old male with sarcoidosis. RESULTS: The patient presented with a 3-year history of bilateral panuveitis thought secondary to his sarcoidosis diagnosed 11 years prior. Shortly before presentation, the patient demonstrated recurrent uveitis with a lack of response to aggressive immunosuppression therapy. At presentation, ocular exam showed significant anterior and posterior inflammation. Fluorescein angiography demonstrated hyperfluorescence of the optic nerve with late and small vessel leakage in the right eye. The patient also described a two-month history of memory and word-finding deficits. An inflammatory and infectious disease work-up was unremarkable. A brain MRI showed multiple enhancing periventricular lesions with vasogenic edema, while a lumbar puncture was negative for malignant cells. A diagnostic pars plana vitrectomy confirmed a diagnosis of large B-cell lymphoma. CONCLUSION: Sarcoidosis and vitreoretinal lymphoma are known masqueraders. Recurrent inflammation typical of sarcoid uveitis may mask a more sinister diagnosis such as vitreoretinal lymphoma. Furthermore, sarcoid uveitis treatment with corticosteroids may transiently improve symptoms but further delay a timely diagnosis of primary vitreoretinal lymphoma.

0.18 MG FLUOCINOLONE ACETONIDE INSERT FOR THE TREATMENT OF CHRONIC POSTOPERATIVE PSEUDOPHAKIC CYSTOID MACULAR EDEMA.

PURPOSE: To report the outcomes of the 0.18 mg fluocinolone acetonide insert (FAi) in the treatment of chronic (>6 months) postoperative cystoid macular edema after cataract surgery. METHODS: This was a retrospective consecutive case series of eyes with chronic postoperative cystoid macular edema treated with the FAi. Visual acuity, intraocular pressure, optical coherence tomography metrics, and supplemental therapies were extracted from the charts before and at 3, 6, 12, 18, and 21 months after FAi placement, when available. RESULTS: Nineteen eyes of 13 patients with chronic postoperative cystoid macular edema after cataract surgery underwent FAi placement with an average follow-up of 15.4 months. Ten eyes (52.6%) had a ≥2-line gain in visual acuity. Sixteen eyes (84.2%) had a ≥20% reduction in optical coherence tomography central subfield thickness. Eight eyes (42.1%) had complete resolution of CME. Improvements in central subfield thickness and visual acuity were sustained throughout individual follow-up. Compared with 18 eyes (94.7%) requiring local corticosteroid supplementation before FAi, only six eyes (31.6%) required supplementation after FAi. Similarly, of the 12 eyes (63.2%) that were on corticosteroid drops before FAi, only 3 (15.8%) required drops after FAi. CONCLUSION: Eyes with chronic postoperative cystoid macular edema after cataract surgery treated with the FAi had improved and sustained visual acuity and optical coherence tomography metrics, along with a reduction in supplemental treatment burden.

Exploring the Therapeutic Potential of Anticancer Heterocyclic Compounds: Role in Nanoscale Pharmacotherapy.

There are a large number of pharmaceutical products in the market containing heterocyclic compounds. Heterocyclic compounds are explored in the field of therapeutics due to their unique physicochemical and pharmacological properties. A large number of heterocyclic compounds existing in the pharmaceutical market have marked anticancer activity and many of them are under research investigations to treat different types of cancers. Anticancer heterocyclic compounds show many shortcomings such as other anticancer agents in bioavailability and site-specific drug delivery resulting in toxicity and decreased patient compliance. These shortcomings can be eliminated by applying the principles of nanotechnology. The present review discloses the biochemical mechanism of action, different biological targets, intrinsic shortcomings, and structure-activity relationships of anticancer heterocyclic compounds. Furthermore, the role of different nanocarrier systems in selective biological targeting and alteration of pharmacokinetic and pharmacodynamic characteristics of anticancer heterocyclic compounds will be discussed in detail.

Functional Imaging of Mitochondria in Age-Related Macular Degeneration Using Flavoprotein Fluorescence.

PURPOSE: Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of age-related macular degeneration (AMD). Oxidized mitochondrial flavoprotein fluorescence (FPF) may serve as a quantifiable biomarker of oxidative stress, reported as either mean score for the entire image (intensity) or variability (heterogeneity). This study examines FPF intensity and heterogeneity across a large patient cohort of various Beckman stages of AMD. METHODS: This study enrolled patients with isolated AMD and healthy control patients with no retinopathy between 2018 and 2021. Multivariate logistic regression analysis included stage of AMD, age, gender, ethnicity, and smoking status. Analysis of Variance test compared mean FPF intensity and heterogeneity between disease states. RESULTS: Four hundred fifty-six eyes (228 AMD eyes, 228 age-matched control eyes) were included in the final multivariate analysis. Intermediate, geographic atrophy (GA), and neovascular AMD correlated with significantly increased FPF intensity (P < 0.001, respectively), while all AMD stages correlated with increased FPF heterogeneity (P < 0.001, respectively). FPF intensity and heterogeneity were significant negative predictors of visual acuity (P = 0.018 and 0.024, respectively). CONCLUSIONS: This prospective observational study further implicates mitochondrial damage in AMD pathophysiology. Long-term clinical trials will be needed to examine the predictive role of FPF imaging in patients over time. [Ophthalmic Surg Lasers Imaging Retina 2023;54:24-31.].

Automation: A revolutionary vision of artificial intelligence in theranostics.

The last two decades have witnessed an extraordinary evolution of automation and artificial intelligence (AI), which has become an integral part of our daily lives. Lately, AI has also been assimilated in the field of medicine to upgrade overall healthcare system and encourage personalized treatment. Theranostics literally meaning combination of diagnosis and therapeutics, is a targeted pharmacotherapy, based on specific targeted diagnostic tests. Numerous theranostic agents/biomarkers are available which can identify the most beneficial treatment, correct dose or predict response to a medicine, thus, maximizing drug efficacy, minimizing toxicity and providing informed treatment choice. For instance, a statistics based Cluster-FLIM technology provides precise data on drug-receptor binding behavior in biological tissues using fluorescence real experimental imaging. Automated Idylla™ qPCR System is another approach in oncology to determine the EGFR mutations at initial stage as well as during the treatment and also assists the oncologist in designing the treatment protocol. Recent incorporation of automation and AI in theranostics has brought a drastic change in early detection and treatment protocols for various diseases such as cancer and diabetes. Also, it leads to quick analysis of number of diverse experimental datum with accuracy. The approach mainly uses computer algorithms to unveil relevant and significant information from clinical data, thereby assisting in making accurate, logical and pertinent decisions. This review highlights the emerging uses/role of automation and AI in theranostics, technical difficulties and focuses on its future prospects to facilitate a patient specific, reliable and efficient pharmacotherapy.

INCIDENCE OF NEW DIABETIC MACULAR EDEMA IN FELLOW EYES OF PATIENTS IN THE VISTA AND VIVID STUDIES.

PURPOSE: To characterize diabetic macular edema (DME) incidence in fellow eyes of patients treated for DME in the study eye. METHODS: This post hoc analysis of VISTA/VIVID data evaluated fellow eyes without DME at baseline through Week 100. Diabetic macular edema presence in the fellow eye was inferred by investigator-reported DME adverse events and use of DME treatments. RESULTS: Over 100 weeks, 44.9%, 44.2%, and 42.9% of fellow eyes developed DME in the intravitreal aflibercept injection 2 mg every 4 weeks (n = 245), intravitreal aflibercept injection 2 mg every 8 weeks (n = 258), and laser control (n = 252) groups, respectively. Mean time to DME development in combined treatment groups was ∼6 months. Multivariable regression analysis confirmed patients with shorter diabetes duration (hazard ratio per 10-year decrease, 1.16; 95% confidence interval, 1.03-1.30; P = 0.0160) and thicker baseline study eye central subfield thickness (hazard ratio per 10- µ m increase, 1.01; 95% confidence interval, 1.01-1.02; P = 0.0002) were at higher risk of developing DME in the fellow eye. CONCLUSION: Among patients with DME in one eye at baseline, almost half developed DME in the fellow eye over 2 years. Shorter duration of diabetes and thicker study eye central subfield thickness were predictors of DME development in the fellow eye.

Immune checkpoint receptor VISTA on immune cells is associated with expression of T-cell exhaustion marker TOX and worse prognosis in renal cell carcinoma with venous tumor thrombus.

PURPOSE: The study aimed to determine the expression of VISTA and TOX within venous tumor thrombus and primary clear cell renal cell carcinoma (ccRCC) and to assess their prognostic value. METHODS: The study enrolled 82 patients with ccRCC and coexisting venous tumor thrombus treated radically from 2012 to 2019 in two tertiary centers. Tissue microarrays were prepared and stained with respective antibodies. The expression of markers was assessed separately on tumor cells (TCs) and/or tumor-associated immune cells (TAICs). RESULTS: TOX expression was positively correlated with the percentage of VISTA-positive TAICs in venous thrombus (p = 0.011), but not in the primary tumor (p = 0.674). High TOX expression was associated with a higher percentage of PD-L1-positive TAICs in both compartments (p = 0.001, p = 0.011, respectively). Positive expression of VISTA on TAICs was associated with PD-L1 expression on TCs (p = 0.005) and TAICs (p = 0.004) in the primary tumor, and only with PD-L1 on TAICs in thrombus (p = 0.006). The presence of VISTA-positive TAICs in venous thrombus was significantly more common in females (p = 0.034), and positively correlated with metastases (p = 0.028), and tumor necrosis (p = 0.013). The cases with VISTA-positive TAICs in venous tumor thrombi had significantly shorter OS than VISTA-negative cases (p = 0.041). CONCLUSION: For the first time, we demonstrated the expression of VISTA- and TOX-positive TAICs in the venous tumor thrombus. We found the association between immune checkpoint receptors and T cell exhaustion markers in both tumor mass and venous thrombus. Finally, we demonstrated that abundance of VISTA-positive TAICs in venous tumor thrombus correlates with worse outcomes in ccRCC.

Biosimilars in Oncology: Latest Trends and Regulatory Status.

Biologic-based medicines are used to treat a variety of diseases and account for around one-quarter of the worldwide pharmaceutical market. The use of biologic medications among cancer patients has resulted in substantial advancements in cancer treatment and supportive care. Biosimilar medications (or biosimilars) are very similar to the reference biologic drugs, although they are not identical. As patent protection for some of the most extensively used biologics begins to expire, biosimilars have the potential to enhance access and provide lower-cost options for cancer treatment. Initially, regulatory guidelines were set up in Europe in 2003, and the first biosimilar was approved in 2006 in Europe. Many countries, including the United States of America (USA), Canada, and Japan, have adopted Europe's worldwide regulatory framework. The use of numerous biosimilars in the treatment and supportive care of cancer has been approved and, indeed, the count is set to climb in the future around the world. However, there are many challenges associated with biosimilars, such as cost, immunogenicity, lack of awareness, extrapolation of indications, and interchangeability. The purpose of this review is to provide an insight into biosimilars, which include various options available for oncology, and the associated adverse events. We compare the regulatory guidelines for biosimilars across the world, and also present the latest trends and challenges in medical oncology both now and in the future, which will assist healthcare professionals, payers, and patients in making informed decisions, increasing the acceptance of biosimilars in clinical practice, increasing accessibility, and speeding up the health and economic benefits associated with biosimilars.

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950-2021 Comprehensive Overview.

Nitroimidazole represents one of the most essential and unique scaffolds in drug discovery since its discovery in the 1950s. It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which was later identified as Azomycin 1 (2-nitroimidazole) and remained in focus until now. This natural antibiotic was the starting point for synthesizing numerous analogs and regio-isomers, leading to several life-saving drugs and clinical candidates against a number of diseases, including infections (bacterial, viral, parasitic) and cancers, as well as imaging agents in medicine/diagnosis. In the present decade, the nitroimidazole scaffold has again been given two life-saving drugs (Delamanid and Pretomanid) used to treat MDR (multi-drug resistant) tuberculosis. Keeping in view the highly successful track-record of the nitroimidazole scaffold in providing breakthrough therapeutic drugs, this comprehensive review focuses explicitly on presenting the activity profile and synthetic chemistry of functionalized nitroimidazole (2-, 4- and 5-nitroimidazoles as well as the fused nitroimidazoles) based drugs and leads published from 1950 to 2021. The present review also presents the miscellaneous examples in each class. In addition, the mutagenic profile of nitroimidazole-based drugs and leads and derivatives is also discussed.

Pathogenic mechanisms and therapeutic promise of phytochemicals and nanocarriers based drug delivery against radiotherapy-induced neurotoxic manifestations.

Radiotherapy is one of the extensively used therapeutic modalities in glioblastoma and other types of cancers. Radiotherapy is either used as a first-line approach or combined with pharmacotherapy or surgery to manage and treat cancer. Although the use of radiotherapy significantly increased the survival time of patients, but its use has been reported with marked neuroinflammation and cognitive dysfunction that eventually reduced the quality of life of patients. Based on the preclinical and clinical investigations, the profound role of increased oxidative stress, nuclear translocation of NF-kB, production of proinflammatory cytokines such as TNF-α, IL-6, IL-ß, increased level of MMPs, increased apoptosis, reduced angiogenesis, neurogenesis, and histological aberrations in CA1, CA2, CA3 and DG region of the hippocampus have been reported. Various pharmacotherapeutic drugs are being used as an adjuvant to counteract this neurotoxic manifestation. Still, most of these drugs suffer from systemic adverse effect, causes interference to ongoing chemotherapy, and exhibit pharmacokinetic limitations in crossing the blood-brain barrier. Therefore, various phytoconstituents, their nano carrier-based drug delivery systems and miRNAs have been explored to overcome the aforementioned limitations. The present review is focused on the mechanism and evidence of radiotherapy-induced neuroinflammation and cognitive dysfunction, pathological and molecular changes in the brain homeostasis, available adjuvants, their limitations. Additionally, the potential role and mechanism of neuroprotection of various nanocarrier based natural products and miRNAs have been discussed.

Evaluation of PD-L1 (E1L3N, 22C3) expression in venous tumor thrombus is superior to its assessment in renal tumor in predicting overall survival in renal cell carcinoma.

BACKROUND: Renal cell carcinoma (RCC) frequently invades renal vein forming neoplastic thrombus. The expression of immune checkpoint receptors in RCC was addressed in multiple studies, but little is known about the expression and prognostic significance of programmed death ligand-1 in tumor thrombus. MATERIAL AND METHODS: The study aimed to evaluate the expression of PD-L1 within venous tumor thrombus and primary tumor using 2 independent antibody clones (22c3 and E1L3N) and to assess its value in predicting overall survival (OS) in the subgroup of patients with RCC and renal vein thrombus. RESULTS: Eighty-two patients with RCC and venous tumor thrombus that underwent nephrectomy were enrolled. The expression of PD-L1 was assessed utilizing tissue microarrays separately on tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). The frequency of PD-L1 expression on TCs and TILs varied between tumor and thrombus compartments and was dependent on the antibody clone used. The expression of PD-L1 on TCs and/or TILs was associated with worse OS irrespectively of the antibody and the analyzed compartment. Nevertheless, the best prognostic performance was noted for the combined assessment of PD-L1 expression on TCs and TILs in venous tumor thrombus with the use of 22c3 antibody. The multivariable Cox regression model predicting OS incorporated PD-L1 22c3 in venous tumor thrombus (hazards ratio [HR] = 3.64, 95% confidence interval [CI] = 1.63-8.14, P = 0.002) and nodal status (HR = 2.88, 95% CI = 1.18-7.03, P = 0.02). CONCLUSIONS: PD-L1 may become a valuable tool for prognostic purposes in this specific subgroup of patients and be incorporated into the respective models qualifying for adjuvant treatment.

Unfolding the effects of decontamination treatments on the structural and functional integrity of N95 respirators via numerical simulations.

Filtering facepiece respirators (FFRs) provide effective protection against diseases spread through airborne infectious droplets and particles. The widespread use of FFRs during the COVID-19 pandemic has not only led to supply shortages, but the disposal of single-use facemasks also threatens the environment with a new kind of plastic pollution. While limited reuse of filtering facepiece respirators has been permitted as a crisis capacity strategy, there are currently no standard test methods available for decontamination before their repeated use. The decontamination of respirators can compromise the structural and functional integrity by reducing the filtration efficiency and breathability. Digital segmentation of X-ray microcomputed tomography (microCT) scans of the meltblown nonwoven layers of a specific N95 respirator model (Venus-4400) after treatment with one and five cycles of liquid hydrogen peroxide, ultraviolet radiation, moist heat, and aqueous soap solution enabled us to perform filtration simulations of decontaminated respirators. The computed filtration efficiencies for 0.3 µm particles agreed well with experimental measurements, and the distribution of particle penetration depths was correlated with the structural changes resulting from decontamination. The combination of X-ray microCT imaging with numerical simulations thus provides a strategy for quantitative evaluation of the effectiveness of decontamination treatments for a specific respirator model.