Novel 3-substituted coumarins inspire a custom pharmacology prediction pipeline: an anticancer discovery adventure.

Aim: This research aims to expand the established pharmacological space of tumor-associated carbonic anhydrases (TACAs) by exploring the synthetically accessible chemical space of 3-substituted coumarins, with the help of in silico pharmacology prediction.Materials & methods: 52 novel 3-substituted coumarins were sketched, prioritizing synthetic feasibility. Their pharmacological potentials were estimated using a custom machine-learning approach. 17 compounds were predicted as cytotoxic against HeLa cells by interfering with TACAs. Those compounds were synthesized and biologically tested against HeLa cells. The three most potent compounds were assayed against multiple carbonic anhydrases, and their enzyme binding mechanism(s) were studied using molecular docking.Results: Experimental results exhibited pronounced consensus with in silico pharmacology predictions.Conclusion: Novel 3-substituted coumarins are herein dispatched to the cancer therapeutics space.

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Global Trial Representation and Availability of Tyrosine Kinase Inhibitors for Treatment of Chronic Myeloid Leukemia.

Background: Evaluating clinical trial representation for countries with different socio-demographic index (SDI) and tyrosine kinase inhibitor (TKI) availability for chronic myeloid leukemia (CML). Methods: CML incidence rates (IRs) and disability-adjusted life years (DALYs) (1999-2019) from the Institute of Health Metrics and Evaluation were analyzed. Trials investigating TKI use in CML were obtained from ClinicalTrials.gov. Site data for eligible trials (N = 30) and DALYs were analyzed. TKI approvals, DALYs, and IRs were summarized by SDI. Results: North America (NA) had significant decreases in annual percent change (APC) in DALYs and incidence rates from 1999 to 2004. IRs were highest in Europe and Central Asia (ECA) and NA, while DALYs were highest in South Asia (SAsia) and Sub-Saharan Africa (SSA). Countries in the high-SDI quintile were likely to have lower DALYs than lower-SDI quintiles. Differences in regional DALYs vs. sites in TKI trials were significant for SAsia, SSA, and ECA. High-SDI countries were included in all 30 trials, and TKI approvals were prominent in high-SDI (142) vs. low-SDI (14) countries. Conclusions: The inclusion of disproportionately affected countries during the design of and recruitment into clinical trials should occur, as should TKI availability. The lack of representation demonstrates healthcare disparities.

Role of Social Support in Screening Colonoscopy/Sigmoidoscopy Uptake among U.S. Adults.

Colorectal cancer (CRC) is a major clinical and public health burden. Screening has been shown to be effective in preventing CRC. In 2021, less than 72% of adult Americans had received CRC screening based on the most recent guidelines. This study examined the relationship between social support and screening colonoscopy or sigmoidoscopy uptake among U.S. adults and the socioeconomic factors that impact the relationship. We conducted a cross-sectional study using the 2021 National Health Interview Survey (NHIS) data for 20,008 U.S. adults to assess the weighted rates of screening colonoscopy or sigmoidoscopy among individuals with strong, some, and weak social support. Adjusted binary logistic regression models were utilized to obtain the weighted odds of receiving a screening colonoscopy or sigmoidoscopy among adults with different levels of social support and socioeconomic status. About 58.0% of adults who reported having colonoscopy or sigmoidoscopy had strong social support, compared to 52.0% who had some or weak social support. In addition, compared to adults with weak social support, the weighted adjusted odds of having colonoscopy or sigmoidoscopy were 1.0 (95% C.I. = 0.994, 0.997; p < 0.001) and 1.3 (95% C.I. = 1.260, 1.263; p < 0.001) for adults with some and strong social support, respectively. Socioeconomic differences were observed in the odds of colonoscopy or sigmoidoscopy uptake based on having strong social support. Having strong social support is an important factor in increasing colonoscopy or sigmoidoscopy screening uptake. Policies and interventions that enhance social support among adults for screening colonoscopy or sigmoidoscopy are warranted.

Representation of the population in need for pivotal clinical trials in lymphomas.

Despite the advances in cancer outcomes, significant health disparities persist. Several new agents have been recently approved for treatment of lymphomas, leading to improved outcomes. Extending the benefits of these new agents starts by adequate enrollment of all affected patient populations. This study aimed to evaluate the extent to which randomized controlled trials (RCTs) match the demographic and geographic diversity of the population affected by lymphoma. Two Food and Drug Administration databases, clinicaltrials.gov, and relevant primary manuscripts were reviewed for drug approval data and demographic representation in RCTs for classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma. Maps showing the distribution and frequency of trial participation relative to disease burden, insurance status, and racial representation were created. Black, Hispanic, and female patients were significantly underrepresented in the RCTs for lymphoma compared with that for the disease burden (3.6% [95% confidence interval (CI), 2.8-5.4] vs 14.6% [95% CI, 13.8-15.3]; 6.7% [95% CI, 5.5-7.9] vs 16.3% [95% CI, 15.5-17.1]; and 39.1% [95% CI, 37.3-40.9] vs 42.7% [95% CI, 42.3-43.1], respectively). White and male patients were overrepresented. More counties with higher mortality rates and racial minority representation had low access to the trials, particularly for cHL in the southern region of the United States. There are significant racial misrepresentations in pivotal RCTs in the United States, and geographic distribution of these trials may not provide easy access to all patients in need. Disparities in enrollment should be corrected to make results applicable to all populations.

Genomic characterization of SARS-CoV-2 in Egypt: insights into spike protein thermodynamic stability.

The overall pattern of the SARS-CoV-2 pandemic so far has been a series of waves; surges in new cases followed by declines. The appearance of novel mutations and variants underlie the rises in infections, making surveillance of SARS-CoV-2 mutations and prediction of variant evolution of utmost importance. In this study, we sequenced 320 SARS-CoV-2 viral genomes isolated from patients from the outpatient COVID-19 clinic in the Children's Cancer Hospital Egypt 57357 (CCHE 57357) and the Egypt Center for Research and Regenerative Medicine (ECRRM). The samples were collected between March and December 2021, covering the third and fourth waves of the pandemic. The third wave was found to be dominated by Nextclade 20D in our samples, with a small number of alpha variants. The delta variant was found to dominate the fourth wave samples, with the appearance of omicron variants late in 2021. Phylogenetic analysis reveals that the omicron variants are closest genetically to early pandemic variants. Mutation analysis shows SNPs, stop codon mutation gain, and deletion/insertion mutations, with distinct patterns of mutations governed by Nextclade or WHO variant. Finally, we observed a large number of highly correlated mutations, and some negatively correlated mutations, and identified a general inclination toward mutations that lead to enhanced thermodynamic stability of the spike protein. Overall, this study contributes genetic and phylogenetic data, as well as provides insights into SARS-CoV-2 viral evolution that may eventually help in the prediction of evolving mutations for better vaccine development and drug targets.

Compounds from the Petroleum Ether Extract of Wedelia chinensis with Cytotoxic, Anticholinesterase, Antioxidant, and Antimicrobial Activities.

Wedelia chinensis is a folk medicine used in many Asian countries to treat various ailments. Earlier investigations reported that the petroleum ether extract of the plant has potential biological activity, but the compounds responsible for activity are not yet completely known. Therefore, the current work was designed to isolate and characterize the compounds from the petroleum ether extract and to study their bioactivities. Four compounds including two diterepenes (-) kaur-16α-hydroxy-19-oic acid (1) and (-) kaur-16-en-19-oic acid (2), and two steroids ß-sitosterol (3), and cholesta-5,23-dien-3-ol (4) were isolated and characterized. Among the compounds, the diterpenes were found to have more biological activities than the steroidal compounds. Compound 1 showed the highest cytotoxicity with LC50 of 12.42 ± 0.87 µg/mL. Likewise, it possesses good antioxidant activity in terms of reducing power. On the contrary, compound 2 exerted the highest antiacetylcholinesterase and antibutyrylcholinesterase activity. Both the diterpenes showed almost similar antibacterial and antifungal activity. The identification of diterpenoid and steroid compounds with multifunctional activities suggests that W. chinensis may serve as an important source of bioactive compounds which should be further investigated in animal model for therapeutic potential in the treatment of different chronic diseases.

Association Among Cystic Volume, Intracystic Pressure, and Histopathological Changes in the Liver in Patients With Choledochal Cyst.

Background Choledochal cyst is a congenital cystic dilatation of the biliary tree. Various aspects of pathophysiology are unclear, particularly with reference to intracholedochal cystic pressure (ICCP) and liver histopathology. This study aimed to determine the relationship among cystic volume, ICCP, and histopathological changes in the liver in patients with choledochal cysts. Methods This cross-sectional study was carried out among 21 patients diagnosed with choledochal cysts, who attended the Department of Pediatric Surgery at Bangabandhu Sheikh Mujib Medical University (BSMMU) from April 2021 to August 2022. Cystic volume was measured pre-operatively using ultrasonography, while ICCP was measured per-operatively with a pressure gauge. Liver histology was assessed through an intraoperative liver biopsy and graded using the meta-analysis of histological data in viral hepatitis (METAVIR) scoring system. The data were analyzed using SPSS version 25.0 (IBM Corporation, Armonk, New York). Frequency and percentages were calculated to present categorical variables, and for quantitative variables, mean, standard deviation (SD), median, and interquartile range (IQR) were calculated. Fisher's exact tests were performed to determine the association between cystic volume, ICCP, and the grading of hepatic fibrosis. A p-value of <0.05 was considered statistically significant. Results The age of the patients ranged from 1 to 12 years, with a mean of 5.0±3.4 years. The male-to-female ratio was 1:4.3. Type I cysts were the most prevalent (71.4%). The median and IQR for cystic volume were 3.4 ml and 1.1-8.2 ml, respectively. The median and IQR for ICCP were 7.46 mmHg and 4.67-9.33 mmHg, respectively. The most frequent grade of fibrosis was F1 (38.1%), followed by F2 (23.8%) and F3 (23.8%). A negative relationship between cystic volume and ICCP was observed, which was statistically significant (p=0.008). A positive relationship was also observed between ICCP and the grading of liver fibrosis, which was statistically significant (p=0.002). Although a negative correlation between cystic volume and grading of liver fibrosis was noted, it was not statistically significant (p=0.198). Conclusions This study reveals significant associations between cystic volume, ICCP, and the grading of liver fibrosis in patients with choledochal cysts. Smaller volume cysts may exhibit higher ICCP, resulting in more pronounced fibrotic changes in the liver.

Evaluation of Colonoscopy and Sigmoidoscopy Utilization for Colorectal Cancer Screening in Georgia, USA.

Colorectal cancer (CRC) is the third most prevalent cancer, and the second most common cancer-related cause of death in the United States (USA). Timely screening reduces both CRC incidence and mortality. Understanding population behaviors and factors that influence CRC screening is important for directing interventions targeted at reducing CRC rates. The 1997-2018 Behavioral Risk Factor Surveillance System (BRFSS) data were analyzed for trends in colonoscopy and sigmoidoscopy utilization for CRC screening among adults in Georgia, USA. Overall, in Georgia, there has been an increase in the prevalence of colonoscopy and sigmoidoscopy utilization from 48.1% in 1997 to 71.2% in 2018 (AAPC = 2.30, p < 0.001). Compared nationally, this increase was less pronounced (from 41.0% in 1997 to 73.7% in 2018 (AAPC = 2.90, p < 0.001) overall for USA). Logistic regression analysis of the 2018 BRFSS data, adjusting for sociodemographic factors, shows that sex (female vs. male [aOR = 1.20, C.I. = 1.05, 1.38]); marital status (couple vs. single [aOR = 1.20, C.I. = 1.04, 1.39]); healthcare coverage (yes vs. no [aOR = 3.86, C.I. = 3.05, 4.88]); age (60-69 years [aOR = 2.38, C.I. = 2.02, 2.80], 70-79 [aOR = 2.88, C.I. = 2.38, 3.48] vs. 50-59 years); education (high school [aOR = 1.32, C.I. = 1.05, 1.65], some post high school [aOR= 1.63, C.I. = 1.29, 2.06], college graduate [aOR = 2.08, C.I. = 1.64, 2.63] vs. less than high school); and income ($25,000-$49,999 [aOR = 1.24, C.I. = 1.01, 1.51], $50,000+ [aOR = 1.56, C.I. = 1.27, 1.91] vs. <$25,000) were all significantly associated with colonoscopy and sigmoidoscopy utilization. In Georgia, a significant increase over time in colonoscopy and sigmoidoscopy utilization for CRC screening was observed pertaining to the associated sociodemographic factors. The findings from this study may help guide tailored programs for promoting screening among underserved populations.

Understanding geographic and racial/ethnic disparities in mortality from four major cancers in the state of Georgia: a spatial epidemiologic analysis, 1999-2019.

We examined geographic and racial variation in cancer mortality within the state of Georgia, and investigated the correlation between the observed spatial differences and county-level characteristics. We analyzed county-level cancer mortality data collected by the Centers for Disease Control and Prevention on breast, colorectal, lung, and prostate cancer mortality among adults (aged ≥ 18 years) in 159 Georgia counties from years 1999 through 2019. Geospatial methods were applied, and we identified hot spot counties based on cancer mortality rates overall and stratified by non-Hispanic white (NH-white) and NH-black race/ethnicity. Among all adults, 5.0% (8 of 159), 8.2% (13 of 159), 5.0% (8 of 159), and 6.9% (11 of 159) of Georgia counties were estimated hot spots for breast cancer, colorectal, lung, and prostate cancer mortality, respectively. Cancer mortality hot spots were heavily concentrated in three major areas: (1) eastern Piedmont to Coastal Plain regions, (2) southwestern rural Georgia area, or (3) northern-most rural Georgia. Overall, hot spot counties generally had higher proportion of NH-black adults, older adult population, greater poverty, and more rurality. In Georgia, targeted cancer prevention strategies and allocation of health resources are needed in counties with elevated cancer mortality rates, focusing on interventions suitable for NH-black race/ethnicity, low-income, and rural residents.

Are Pivotal Clinical Trials for Drugs Approved for Leukemias and Multiple Myeloma Representative of the Population at Risk?

PURPOSE: There are significant disparities in care and outcomes for patients with leukemias and multiple myeloma (MM). To evaluate the extent to which clinical trials (CTs) match the demographic and geographic diversity of populations affected by leukemias and MM. METHODS: CTs leading to drug approval were identified from the US Food and Drug Administration databases. Demographic and geographic data were collected from ClinicalTrials.gov and primary manuscripts. Standard descriptive statistics were used to summarize the data in frequencies and proportions, including 95% CIs, by race, ethnicity, sex, and malignancy subtypes. RESULTS: A total of 41 (67.2%) trials leading to drug approval reported data on race and 20 (48.8%) on ethnicity. These trials included 13,731 patients, of whom 11,209 (81.6%) were White. Among minorities, Asian-Pacific Islanders and Blacks had the highest representation in chronic myeloid leukemia, 147 (12.7%) and 61 (5.3%), and lowest in chronic lymphocytic leukemia, 55 (3%) and 20 (1.1%), respectively. Proportions for Blacks, Native Americans, and Hispanics were significantly low, reflecting under-representation in trials compared with the proportion in the general population. Females were also under-represented in acute myeloid leukemia (44.7% v 60.5%, P < .0001), and males in MM (55.3% v 60.2%, P < .0001) and chronic myeloid leukemia (55.2% v 62.9%, P < .0001). The geographic distribution of trials showed inadequate regional and state participation compared with mortality for all malignancies except MM. CONCLUSION: There are significant demographic and geographic under-representation and imbalances in pivotal CTs leading to drug approvals for leukemias and MM compared with the population affected. These disparities need to be addressed to make results applicable to all relevant populations.

Evaluation of portal venous system in post splenectomised beta-thalassemic children: A prospective study in a tertiary care hospital.

Background: Splenectomy is a palliative management technique in children with ß-thalassemia. Portal thrombosis is the most dreaded complication after splenectomy that requires fast diagnosis, effective therapy, and good follow-up to prevent protal hypertension. Thus, there is the importance of constant evaluation of portal venous system through Color Doppler Ultrasound. This cohort study aimed to observe the changes in the portal venous system in post-splenectomised ß-thalassemic children. Material and methods: This is a prospective observational cohort study carried out on all the pediatric patients who have undergone splenectomy in Bangabandhu Sheikh Mujib Medical University, Dhaka Bangladesh from 2017 to 2019 for ß-thalassemia. The color doppler of the portal venous system was done within the 7th to 10th post-operative day and after 3 months. Outcomes like mean the caliber of the portal vein, mean velocity within the portal vein, and color Doppler findings like Portal Vein Thrombosis (PVT) and Pathological change in Mean Volume (PMV) were calculated and compared in two headings: pre-operative period and postoperative period (7-10 POD and 3 months) with the help of paired t-test. Results: Twenty-Eight ß-thalassemia patients with a mean age of 10.43 ± 3.91 years planned to undergo splenectomy were included in our study. The pre-operative mean caliber and mean velocity of the portal vein were not statistically significant when compared after the postoperative period (7-10 POD and 3 months). But, continuous changes in portal vein were seen that could lead to normalization or pathological changes. Conclusion: There are physiological and pathological changes in portal vein following splenectomy that could lead to varied complications like portal vein thrombosis and portal hypertension. Color Doppler Ultrasound findings along with close follow-up help in minimizing the pathological changes and complications.

Polyphenolics with Strong Antioxidant Activity from Acacia nilotica Ameliorate Some Biochemical Signs of Arsenic-Induced Neurotoxicity and Oxidative Stress in Mice.

Neurotoxicity is a serious health problem of patients chronically exposed to arsenic. There is no specific treatment of this problem. Oxidative stress has been implicated in the pathological process of neurotoxicity. Polyphenolics have proven antioxidant activity, thereby offering protection against oxidative stress. In this study, we have isolated the polyphenolics from Acacia nilotica and investigated its effect against arsenic-induced neurotoxicity and oxidative stress in mice. Acacia nilotica polyphenolics prepared from column chromatography of the crude methanol extract using diaion resin contained a phenolic content of 452.185 ± 7.879 mg gallic acid equivalent/gm of sample and flavonoid content of 200.075 ± 0.755 mg catechin equivalent/gm of sample. The polyphenolics exhibited potent antioxidant activity with respect to free radical scavenging ability, total antioxidant activity and inhibition of lipid peroxidation. Administration of arsenic in mice showed a reduction of acetylcholinesterase activity in the brain which was counteracted by Acacia nilotica polyphenolics. Similarly, elevation of lipid peroxidation and depletion of glutathione in the brain of mice was effectively restored to normal level by Acacia nilotica polyphenolics. Gallic acid methyl ester, catechin and catechin-7-gallate were identified in the polyphenolics as the major active compounds. These results suggest that Acacia nilotica polyphenolics due to its strong antioxidant potential might be effective in the management of arsenic induced neurotoxicity.

Comparison of Urban-Rural Readmission Rates After Colorectal Cancer Surgery: Findings From a Privately Insured Population.

OBJECTIVES: We assessed the 30-day readmission rate of a privately insured population diagnosed with colorectal cancer (CRC) who had primary tumor resection in rural and urban communities. METHODS: Claims data of people aged <65 with a diagnosis of CRC between 2012 and 2016 and enrolled in a private health plan administered by BlueCross BlueShield of Nebraska were analyzed. Readmission was defined as the number of discharged patients who were readmitted within 30 days, divided by all discharged patients. Multivariate logistic regression was used to estimate the factors associated with readmission. RESULTS: The urban population had a higher readmission rate (11%) than the rural population (8%). Although the adjusted odds ratio showed that there is no difference in readmission between rural and urban residents, patients with a Charlson Comorbidity Index (CCI) of >1 were more likely than those without CCI to be readmitted (OR 3.59, 1.41-9.11). Patients with open vs. laparoscopic surgery (OR 2.80, 1.39-5.63) and those with an obstructed or perforated colon vs. none (OR 7.17, 3.75-13.72) were more likely to be readmitted. CONCLUSIONS: Readmission after CRC surgery occurs frequently. Interventions that target the identified risk factors should reduce readmission rates in this privately insured population.

Localized amyloidosis in usual-type vulvar intraepithelial neoplasia: High-risk HPV association and potential clinical significance. A series of 45 cases.

Localized cutaneous amyloidosis was reported recently in association with vulvar squamous intraepithelial neoplasia (VIN). High-risk human papillomavirus (hrHPV) type 16 is the most commonly reported subtype found in usual-type VIN. However, it is unknown whether any hrHPV subtype(s) is/are prevalent in simultaneous squamous intraepithelial lesions and localized amyloidosis in the same individual - the subject matter of this report. To observe the potential clinical significance, study cases were followed and compared to usual-type VINs without amyloid deposition. Of 45 patients of usual-type VINs associated with amyloidosis, 33 had detectable hrHPV, and 12 were negative. HPV 16 alone or in combination with HPV 31 accounted for 72%, HPV 51 alone accounted for 2% of the cases, and 26% were negative for hrHPV. Lack of demonstrable hrHPV in a significant proportion of cases (26%) raises the possibility of a novel or presently undetected hrHPV subtype. Five of the total 22 (23%) patients with amyloid had either Squamous cell carcinoma or high-grade VIN on follow-up. In contrast, 14 of 18 (78%) patients exhibiting lesions without amyloid had disease on follow-up. These findings may indicate that amyloid deposition may represent a feature of regression or a potential favorable prognostic indicator.

Factors Associated With Treatment Refusal and Impact of Treatment Refusal on Survival of Patients With Small Cell Lung Cancer.

BACKGROUND: With fewer than 7% of patients with small cell lung cancer (SCLC) surviving 5 years after diagnosis, the receipt of recommended treatment is of utmost importance for patient survival. Nevertheless, treatment refusal by patients with SCLC has not been studied well. Our study examined factors associated with treatment refusal and the effect of refusal on patient survival. METHODS: From the National Cancer Database, we analyzed data of 107,988 patients with SCLC diagnosed between 2003 and 2012. Treatment refusals were analyzed separately for chemoradiotherapy among patients with limited stage disease (LS-SCLC) and chemotherapy among those with extensive stage disease (ES-SCLC). We used logistic regression to investigate factors associated with treatment refusal. We estimated survival probability using the Kaplan-Meier method and compared survival of those who received and refused treatment using Cox proportional hazards regression analysis. RESULTS: The refusal rates of chemoradiotherapy among patients with LS-SCLC and chemotherapy among those with ES-SCLC were 1.34% and 4.70%, respectively. From 2003 to 2012, trends show an increase of refusals, especially among the patients with ES-SCLC who were recommended chemotherapy. Multivariable analyses showed that in both SCLC groups, older age at diagnosis (>70 years), female gender, uninsured status, and presence of comorbidities were associated with treatment refusals. Patients with LS-SCLC who refused chemoradiotherapy had a higher risk of mortality than those who received treatment (HR, 4.96; 95% CI, 4.45-5.53); the median survival of those who refused treatment was 3 months vs 18 months for those who received it (P < .001). Similarly, patients with ES-SCLC who refused chemotherapy had a higher risk of mortality than those who received treatment (HR, 3.69; 95% CI, 3.48-3.92); the median survival was 1 month vs 7 months, respectively (P < .001). CONCLUSIONS: Treatment refusal among patients with SCLC was associated with worse survival. Strategies to increase patient acceptance of the recommended treatment need to be studied further.

Colorectal Cancer Screening Uptake: Differences Between Rural and Urban Privately-Insured Population.

Earlier studies investigated rural-urban colorectal cancer (CRC) screening disparities among older adults or used surveys. The objective was to compare screening uptake between rural and urban individuals 50-64 years of age using private health insurance. Data were analyzed from 58,774 Blue Cross Blue Shield of Nebraska beneficiaries. Logistic regression was used to assess the association between rural-urban and CRC screening use. Results indicate that rural individuals were 56% more likely to use the Fecal Occult Blood Test (FOBT) compared with urban residents, but rural females were 68% less likely to use FOBT. Individuals with few Primary Care Physician (PCP) visits and rural-women are the least to receive screening. To enhance CRC screening, a policy should be devised for the training and placement of female PCP in rural areas. In particular, multilevel interventions, including education, more resources, and policies to increase uptake of colorectal cancer screening, are needed. Further research is warranted to investigate barriers to CRC screening in rural areas.

Impact of time-to-treatment on overall survival of non-small cell lung cancer patients-an analysis of the national cancer database.

BACKGROUND: The association between time-to-treatment and outcomes for lung cancer has not been conclusively established. In this study, we evaluated the effect of time-to-treatment on the overall 5-year survival of patients with non-small cell lung cancer (NSCLC) with cancer stage at diagnosis. METHODS: We analyzed data in the National Cancer Data Base for adult patients newly diagnosed with NSCLC in 2003-2011 (N=693,554). Extended Cox regression with counting process was used to model the effect of time-to-treatment on survival, adjusted for demographic and clinical factors. Multivariable analyses were performed separately for the groups with different stages at diagnosis. Time-to-treatment was defined as the interval between diagnosis and treatment initiation, with the categories of (I) 0 day, (II) 1 day-4 weeks, (III) 4.1-6.0 weeks, and (IV) >6 weeks (the 1 day-4 weeks group was considered the reference group). RESULTS: Compared to treatment initiated between 1 day and 4 weeks after diagnosis, time-to-treatment at 4.1-6.0 weeks was associated with a lower risk of death for patients with early-stage cancer [adjusted HR (aHR), 0.84 (95% CI, 0.82-0.85)], with locally advanced cancer [aHR, 0.82 (95% CI, 0.80-0.83)], and with metastatic cancer [aHR, 0.75 (95% CI, 0.74-0.76)]. Similarly, a lower risk of death was associated with time-to-treatment longer than 6 weeks for patients with any cancer stage at diagnosis. However, a subset analysis for early-stage patients who received surgery only showed that extended time-to-surgery was associated a higher risk of death [aHR 4.1-6.0 weeks, 1.06 (95% CI, 1.03-1.09); aHR>6 weeks 1.17 (95% CI, 1.14-1.20)]. CONCLUSIONS: The findings show that, although time-to-treatment should not be compromised, it is imperative to ensure that patients receive optimal pre-treatment assessments rather than rushing the treatment. Future research should focus on examining clinical characteristics to determine an optimal time-to-treatment to achieve the best possible survival for NSCLC patients.

Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines.

OBJECTIVE: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. METHODS: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. RESULTS: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9µM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 µM). CONCLUSION: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.