Synthesis, Biological and Molecular Docking Studies of Thiazole-Thiadiazole derivatives as potential Anti-Tuberculosis Agents.

Tuberculosis remains a global health threat, with increasing infection rates and mortality despite existing anti-TB drugs. The present work focuses on the research findings regarding the development and evaluation of thiadiazole-linked thiazole derivatives as potential anti-tuberculosis agents. We present the synthesis data and confirm the compound structures using spectroscopic techniques. The current study reports twelve thiazole-thiadiazole compounds (5 a-5 l) for their anti-tuberculosis and related bioactivities. This paper emphasizes compounds 5 g, 5 i, and 5 l, which exhibited promising MIC values, leading to further in silico and interaction analysis. Pharmacophore mapping data included in the present analysis identified tubercular ThyX as potential drug targets. The compounds were evaluated for anti-tubercular activity using standard methods, revealing significant MIC values, particularly compound 5 l, with the best MIC value of 7.1285 µg/ml. Compounds 5 g and 5 i also demonstrated moderate to good MIC values against M. tuberculosis (H37Ra). Structural inspection of the docked poses revealed interactions such as hydrogen bonds, halogen bonds, and interactions containing Pi electron cloud, shedding light on conserved interactions with residues like Arg 95, Cys 43, His 69, and Arg 87 from the tubercular ThyX enzyme.

Evaluation of the 3D Technology in the Auto-transplantation: An Original Research.

Introduction: Using three-dimensional printed duplicates of the donor teeth, three-dimensional auto-transplantation is a medical procedure that moves a tooth from one location inside a patient to another. The intraoperative practicability during 3D auto-transplantation of teeth was evaluated in the present study. Material and Methods: A prospective multicenter clinical study was done among the subjects. "Preoperative cone-beam computed tomography imaging," "computer-assisted design (CAD)," and "computer-assisted manufacturing (CAM)" were used in all operations to make a 3D duplicate of the donor teeth. The clinical parameters that were evaluated were the time required for the fit, number of attempts to fit, and intra-operative experience. Results: Canines, premolars, molars, and one extra tooth were all transplanted during the 200 auto-transplantation surgeries among 152 subjects. An initial satisfactory fit of the donor tooth and an extra-alveolar time of less than one minute were achieved in 80% of the surgeries. The extra-alveolar time exceeded 3 minutes in ten teeth. Difficulties that were faced were related to the imaging, patient cooperation, and the bone quality. Conclusions: The application of the duplicate teeth by 3D printing of a donor tooth all through auto-transplantation techniques reduced the time the tooth stays extra-alveolar as well as the efforts at transplant fitting during implantation. This allowed for more challenging surgeries as well as a speedy and reliable therapy.

Synthesis, biological evaluation, and molecular docking of novel 1,3,4-substituted-thiadiazole derivatives as potential anticancer agent.

In an attempt to develop potent anti-cancer agents, a new 1,3,4-substituted-thiadiazole derivatives (8b-g), starting from 4-substituted-thiazol-2-chloroacetamides (4b-g), were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the hepatocellular carcinoma (HEPG-2), human lung carcinoma (A549), human breast carcinoma (MCF-7) and pseudo-normal human embryonic liver (L02) cancer cell lines by an MTT assay. Among all synthesized compounds, compound 8d showed the potent anti-cancer activities with GI50 values of 2.98, 2.85 and 2.53 µM against MCF-7, A549 and HepG-2 cell lines respectively as compared to standard drug Doxorubicin. Furthermore, molecular modelling studies have spotlighted the anchoring role of 1,3,4-substituted-thiadiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. Therefore, these results can provide promising starting points for further development of best anti-cancer agents.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE): A rare pathology with unusual behavior.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a benign lesion of oral mucosa with unclear pathogenesis. The etiology of TUGSE is still not clear, but traumatic irritation is considered to be the most likely cause. The lesion is usually self-limiting and regresses on its own or after biopsy and recurrence or reappearance of lesion is rare. We present a very unusual behavior of this lesion where lesion not only reappeared/recurred within few days of complete excision, but was larger than initial lesion and regressed after incisonal biopsy of the recurrent lesion. This presentation is rarely reported.

Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability.

CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types.

A maize line resistant to herbivory constitutively releases (E) -beta-caryophyllene.

Various pests, such as those in the order Lepidoptera, frequently feed on young maize (Zea mays) plants and pose a significant threat to plant development and survival. To manage this problem, maize generates a wide variety of responses to attack by pests, from activation of wound-response pathways to the release of volatile compounds. Mp708, an inbred line resistant to feeding by the larvae of the fall armyworm (Spodoptera frugiperda J.E. Smith Lepidoptera: Noctuidae), has been developed through traditional breeding methods, but its underlying mechanisms of resistance are still not completely understood. Mp708 has been shown to have a moderately high constitutive expression of jasmonic acid (JA) before infestation by fall armyworm. However, Tx601, a genotype susceptible to feeding by fall armyworm, activates JA pathway only in response to feeding, suggesting that Mp708 is "primed" to respond swiftly to an attack. Current research indicates that fall armyworm show a lack of preference to feeding on Mp708, leading to the hypothesis that volatiles constitutively released by the plant may also play an important role in its resistance. Analysis of volatiles released by Mp708 and Tx601 in the presence and absence of fall armyworm larvae identified (E)-beta-caryophyllene, a terpenoid associated with resistance, released constitutively in Mp708. Fall armyworm fed samples of both Mp708 and Tx601 showed high transcript number of tps23, the gene responsible for the synthesis of (E)-beta-caryophyllene. In addition, fall armyworm larvae show a preference for Tx601 whorl tissue over Mp708 tissue, and the dosage of Tx601 whorl with (E)-beta-caryophyllene repels the fall armyworm.

Self-immolative Linkers in Prodrugs and Antibody Drug Conjugates in Cancer Treatment.

BACKGROUND: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety. OBJECTIVE: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells. METHODS: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years uptill 2020. RESULTS: The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione) through over-expressed enzymes (cathepsin, plasmin, ß-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site. CONCLUSION: This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promise in therapeutic applications.

Epidemiology and Clinical Characteristics of Individuals with Hepatitis C Virus Infection in the United States, 2017-2019.

INTRODUCTION: Hepatitis C virus (HCV) is the most common bloodborne chronic infection in the US. Following approval of highly effective, direct-acting antivirals in 2014, the diagnostic and treatment rates for HCV infection in the US have evolved. This study assessed the number of individuals with HCV screening or diagnostic testing and the clinical characteristics and treatment of HCV-infected individuals between 2017 and 2019. METHODS: Individuals screened for HCV antibody and/or tested for HCV ribonucleic acid (RNA) from 2017 to 2019 by two large US laboratory companies were included in this analysis. Clinical characteristics, such as HCV genotype, fibrosis stage, HIV coinfection and demographics, were assessed in HCV RNA-positive individuals. HCV treatment and subsequent achievement of sustained virologic response were imputed using data-driven algorithms based on successive viral load decline and negativity. RESULTS: From 2017 to 2019, the number of individuals tested for HCV antibody increased by 5.7%, from 7,580,303 in 2017 to 8,009,081 in 2019. The percentage of individuals tested who were HCV antibody positive was stable, ranging from 5.0% in 2017 to 4.9% in 2018 and 2019. The number of HCV RNA-positive individuals decreased by 5.0% from 382,500 in 2017 to 363,532 in 2019. Of HCV RNA-positive individuals, the proportions with genotype (GT) 3 and minimal fibrosis increased over time; proportions of individuals aged < 40 years increased, while the proportion aged 50 to 59 years decreased. Treatment rates increased from 23.4% in 2017 to 26.8% in 2019. CONCLUSIONS: The percentage of HCV antibody-positive individuals remained stable from 2017 to 2019. The number of individuals tested HCV RNA positive decreased over the years. Demographics shifted toward a younger population with less fibrosis and higher rates of GT3. More than 70% of diagnosed individuals were not treated during this interval, highlighting a need for unfettered access to treatment.

Synthesis and Biological Evaluation of (-) and (+)-Spiroleucettadine and Analogues.

A second-generation enantiospecific synthesis of spiroleucettadine is described. The original reported antibacterial activity was not observed when the experiment was repeated on the synthetic samples; however, significant anti-proliferative activity was uncovered for both enantiomers of spiroleucettadine. Comparison of the optical rotational data and ORD-CD spectra of both enantiomers and the reported spectrum from the natural source have not provided a definitive answer regarding the absolute stereochemistry of naturally occurring spiroleucettadine. Efforts then focussed on alteration at the C-4 and C-5 positions of the slightly more active (-)-spiroleucettadine. Ten analogues were synthesised, with three analogues found to possess similar anti-proliferative profiles to spiroleucettadine against the H522 lung cancer cell line.

Patterns of Prescription Opioid Use in Women With Endometriosis: Evaluating Prolonged Use, Daily Dose, and Concomitant Use With Benzodiazepines.

OBJECTIVE: To examine opioid use, opioid prescribing patterns, and timing of the first opioid prescription in endometriosis patients compared with matched women in the control group without endometriosis. METHODS: We conducted a retrospective analysis of the Clinformatics Datamart database. Women diagnosed with endometriosis from January 2006 through December 2016 and aged 18-49 years were compared with women in the control group matched on age, region, race, insurance payer, and plan type. Key outcomes included: filled prescription for an opioid, multiple opioid prescriptions, number of days' supply, daily dose (morphine milligram equivalents), and concomitant opioid and benzodiazepine prescriptions. Cohorts were descriptively analyzed using t- and χ statistics and multivariable regression analyses yielded adjusted relative risk (RR) ratios and 95% CI. RESULTS: The study sample included 53,847 endometriosis patients and 107,694 patients in the control group. The mean age was 38 years, 62.4% of patients were white, and 51.6% lived in the South. Women in the endometriosis case group, compared with women in the control group, were more likely to fill an opioid prescription (42,705 [79.3%] women in the case group vs 26,106 [24.2%] women in the control group; adjusted RR ratio 2.91; 2.87-2.94), had higher likelihood of filling prescriptions with a dose of 50 morphine milligram equivalents or more (24,544 [45.6%] vs 10,463 [9.7%]; adjusted RR ratio 4.07; 3.98-4.16) or 100 morphine milligram equivalents or more (8,013 [14.9%] vs 3,582 [3.3%]; adjusted RR ratio 3.56; 3.43-3.70). Women in the case group were more likely to have concomitant opioid and benzodiazepine prescriptions (5,453 [10.1%] vs 3,711 [3.5%]; adjusted RR ratio 1.95; 1.88-2.03) and to have used these drugs concurrently for at least 30 days (1,596 [3.0%] vs 1,265 [1.2%]; adjusted RR ratio 1.43; 1.34-1.52) or at least 90 days (875 [1.6%] vs 777 [0.7%]; adjusted RR ratio 1.27; 1.17-1.37). Similar results were obtained after excluding opioid prescriptions received during a 30-day postsurgery window. CONCLUSION: Women with endometriosis had higher probabilities of prolonged use of opioids and concomitant use with benzodiazepines compared with women without this condition. FUNDING SOURCE: This study was funded by AbbVie, Inc.

Adherence to thyroid hormone replacement therapy: a retrospective, claims database analysis.

OBJECTIVE: The objective of this analysis was to compare adherence at 6 months and 12 months across levothyroxine formulations for patients with hypothyroidism. METHODS: This retrospective analysis utilized insurance claims data from a commercially insured population from January 1, 2000 through March 31, 2016. Patients were included if they were diagnosed with hypothyroidism and initiated treatment with generic levothyroxine, Levoxyl, Synthroid, Unithroid, or Tirosint. Patients were excluded if they were younger than age 18, were diagnosed with thyroid cancer, received a prescription for liothyronine, or did not have continuous insurance coverage over the study period. Adherence, defined by the proportion of days covered (PDC) ≥ 80%, was examined using multivariable analyses for both 6 and 12 months post-initiation on therapy Results: The study identified 580,331 patients who fit the study criteria. At 6 months, 40.3% of patients were found to be non-adherent, while 51.9% were non-adherent at 12 months. Synthroid was associated with significantly higher adherence compared to all other levothyroxine formulations at both 6 and 12 months. Compared to generic levothyroxine, the likelihood of being adherent at 12 months was highest for Synthroid (OR = 1.44; 95% CI = 1.43-1.46), followed by Levoxyl (OR = 1.20 95% CI = 1.17-1.23). Tirosint and Unithroid were associated with significantly lower adherence at 12 months compared to generic levothyroxine (OR = 0.65; 95% CI = 0.57-0.75 and OR = 0.79; 95% CI = 0.71-0.89, respectively). CONCLUSIONS: This large, retrospective real-world study demonstrated that adherence to levothyroxine remains a concern among patients with hypothyroidism, and that differences in adherence may exist across levothyroxine formulations.

Development of a Comprehensive Dataset of Hepatitis C Patients and Examination of Disease Epidemiology in the United States, 2013-2016.

INTRODUCTION: Chronic infection with hepatitis C virus (HCV) is a leading cause of liver disease and infectious disease deaths. While recent and emerging treatment options for HCV patients have enabled higher rates of sustained virologic response (SVR), the demographic, clinical, geographic, and payer characteristics of the estimated 3.4 million chronic HCV patients in the USA are poorly understood. The goal of this study was to create a dataset describing the current HCV patient landscape in the USA. METHODS: Data from two large national laboratory companies representing the majority of US patients screened for HCV antibody and/or tested for HCV RNA from 2013 through 2016 were organized into the present study dataset. Age, gender, payer channel, 3-digit ZIP code and ordering physician specialty, and 3-digit ZIP code information were available for all patients. Among RNA-positive patients, additional clinical characteristics included HCV genotype, fibrosis stage, renal function, and HIV status. Initiating treatment and attaining cure were imputed using data-driven algorithms based on successive RNA viral load measurements. RESULTS: The number of RNA-positive HCV patients increased from 200,066 patients in 2013 to 469,550 in 2016. The availability of clinical data measurements and rates of treatment initiation increased over the study period, indicating improved care engagement for HCV patients. Treatment and cure rates varied by age, disease severity, geographic location, and payer channel. Sensitivity and specificity of the cure prediction algorithms were consistently above 0.90, validating the robustness of the data imputation approach. CONCLUSION: This is the largest, most comprehensive dataset available to describe the current US HCV patient landscape. Our results highlight that the epidemiology of HCV is evolving with an increasing number of patients who are younger and have milder disease than described in previous years. Results of this study should help guide efforts toward the elimination of HCV in this country. Future work will focus on factors associated with varying treatment and cure patterns and describing recent changes in the HCV patient landscape. FUNDING: AbbVie. Plain language summary available for this article.

Recovery from Heat Shock in Heat-Tolerant and Nontolerant Variants of Creeping Bentgrass.

Recovery from the heat-shock response was tested in heat-tolerant (selected bentgrass [SB]) and nontolerant (nonselected bentgrass [NSB]) variants of creeping bentgrass (Agrostis palustris Huds.) SB increased incorporation of radioactive amino acids into protein 2 h earlier than NSB when leaf blades were incubated at the recovery temperature following heat shock. Electrophoresis indicated that heat-shock protein (HSP) synthesis decreased and normal protein synthesis increased at 4 h in SB and at 6 to 8 h in NSB. Increased synthesis of normal proteins was not due to increased abundance of normal mRNAs, which were equivalent in SB and NSB at 4 h. But at 4 h, more of the normal mRNA population was associated with polysomes in SB than in NSB. Synthesis of HSP70 and HSP18 decreased earlier in SB than in NSB. The decreased synthesis of these HSPs appeared to be correlated with decreased mRNA abundance. But at 4 h, some of the HSP18 mRNA may have been associated with heat-shock granules in SB. Synthesis of HSP25 continued through the 8-h recovery in both variants. Although the abundance of HSP25 was equivalent in SB and NSB during heat shock and recovery, more HSP25 mRNA was associated with polysomes in SB than in NSB.

Heat-Shock Response in Heat-Tolerant and Nontolerant Variants of Agrostis palustris Huds.

The heat-shock response in heat-tolerant variants (SB) and non-tolerant variants (NSB) of creeping bentgrass (Agrostis palustris Huds.) was investigated. Both variants were derived from callus initiated from a single seed of the cultivar Penncross. SB and NSB synthesized heat-shock proteins (HSPs) of 97, 83, 70, 40, 25, and 18 kD. There were no major differences between SB and NSB in the time or temperature required to induce the heat-shock response. When the HSPs synthesized by SB and NSB were analyzed by two-dimensional gel electrophoresis, it was apparent that SB synthesized two to three additional members of the HSP27 family, which were smaller (25 kD) and more basic than those synthesized by NSB. Analysis of F1 progeny of NSB x SB indicated that 7 of the 20 progeny did not synthesize the additional HSP25 polypeptides. These progeny were significantly less heat tolerant than progeny that did synthesize the additional HSP25 polypeptides. The X2 test of independence (X2 = 22.45, P < 0.001) indicated that heat tolerance and the presence of the additional HSP25 polypeptides are linked traits.

Early View of the Effectiveness of New Direct-Acting Antiviral (DAA) Regimens in Patients with Hepatitis C Virus (HCV).

INTRODUCTION: Clinical trials have demonstrated the efficacy of all-oral direct-acting antiviral (DAA) regimens in the treatment of patients infected with hepatitis C virus (HCV). This study assessed real-world effectiveness of two recently approved regimens; paritaprevir/ritonavir/ombitasvir; dasabuvir (3D), and sofosbuvir/ledipasvir (SOF/LDV) in patients with HCV genotype 1. METHODS: A retrospective analysis of administrative claims data (IMS Health Patient-Centric Data Warehouse/Medivo database) from October 1, 2013 to August 14, 2015 was conducted. Patients ≥19 years of age with a HCV genotype 1 infection, a prescription fill for 3D or SOF/LDV, and ≥1 HCV viral load (VL) assessment from weeks 4-30 post-treatment were selected for analysis. Percentages of patients achieving sustained virologic response (SVR; defined as HCV RNA ≤43 IU/mL) were determined. Unadjusted SVR rates were compared between treatment groups using Fisher's exact tests. SVR rates were also assessed using multivariate regression with adjustment for age group, sex, and treatment history. Analyses were repeated for a subset of patients with VL assessment from 12 to 30 weeks post-treatment. RESULTS: A total of 1707 (44 3D and 1663 SOF/LDV) patients were included. The majority (60%) were male, 49% were aged 55-64 years, and 97% were treatment-naïve 1 year prior to index. The unadjusted relative risk (RR) for achieving SVR in patients treated with SOF/LDV compared with 3D was 0.98%, 95% confidence interval (CI): 0.93-1.02. After adjusting for the baseline covariates, the RR was 0.98%, 95% CI: 0.94-1.03. CONCLUSIONS: In this early view of real-world data, effectiveness of all-oral DAA regimens in HCV genotype 1 patients was concordant with results from registration trials. SVR rates were similar for the two regimens. Further studies are needed to confirm these results. FUNDING: AbbVie, Inc.

The impact of ribavirin on real-world adherence rates in hepatitis C patients treated with sofosbuvir plus simeprevir.

BACKGROUND: Combination therapy with sofosbuvir (SOF) and simeprevir (SIM) is used to treat patients with hepatitis C virus infection. It is currently unknown whether adding ribavirin (RBV) to SOF + SIM, which raises the pill count from two up to eight pills a day, impacts adherence. The aim of this study is to examine the impact of pill count on real-world adherence rates in patients treated with SOF + SIM with and without RBV. METHODS: This retrospective study assessed composite adherence to SOF and SIM over 12 weeks of treatment for two cohorts of hepatitis C patients: one initiating SOF + SIM therapy, and the other initiating SOF + SIM + RBV therapy. Analyses were conducted using MarketScan(®) and Optum US commercial pharmacy claims and enrollment data. Adherence was adjusted by treatment regimen, age, sex, co-pay, presence/absence of cirrhosis, treatment history, and Charlson Comorbidity Index. RESULTS: There was a significant difference in composite unadjusted and adjusted adherence rates for SOF and SIM for the SOF + SIM vs SOF + SIM + RBV cohorts based on MarketScan data (unadjusted, 92.6% and 89.7%, respectively; P=0.0423; adjusted, 92.2% and 88.7%, respectively; P=0.0176), but not based on Optum data (unadjusted, 94.8% and 95.6%, respectively; P=0.5618; adjusted, 94.8% and 95.1%, respectively; P=0.8589). In the MarketScan and Optum databases, there were no statistical differences in unadjusted and adjusted adherence rates for SOF. Unadjusted and adjusted adherence rates for SIM were mixed, as they were for composite adherence. CONCLUSION: The impact of the addition of RBV to SOF + SIM therapy was mixed. The impact of RBV on SOF adherence was not significant in either database.

The use of polymerase chain reaction assay to diagnose proliferative gill disease in channel catfish (Ictalurus punctatus).

To assess the potential of a polymerase chain reaction (PCR) assay as a diagnostic tool in the detection of proliferative gill disease (PGD) in channel catfish (Ictalurus punctatus), PCR assays were compared with the traditional diagnostic methods of gill wet mounts and histology. A PCR assay using primers for Aurantiactinomyxon ictaluri, the actinospore associated with PGD, was performed with tissues from fish from commercial ponds. Using histology as the "gold standard," the sensitivity, specificity, and accuracy of the PCR assay were all >90%. In comparison, the wet mount examinations had a lower sensitivity and specificity. Using the chi-square test and a test for strength of association, there was a significant, strong association between results obtained by PCR and those obtained by the other 2 methods. These results demonstrate that the PCR assay is a good diagnostic tool for the detection of PGD.