Facile synthesis of N- (4-bromophenyl)-1- (3-bromothiophen-2-yl)methanimine derivatives via Suzuki cross-coupling reaction: their characterization and DFT studies

A variety of imine derivatives have been synthesized via Suzuki cross coupling of N-(4-bromophenyl)-1-(3-bromothiophen-2-yl)methanimine with various arylboronic acids in moderate to good yields (58–72%). A wide range of electron donating and withdrawing functional groups were well tolerated in reaction conditions. To explore the structural properties, Density functional theory (DFT) investigations on all synthesized molecules (3a–3i) were performed. Conceptual DFT reactivity descriptors and molecular electrostatic potential analyses were performed by using B3LYP/6-31G(d,p) method to explore the reactivity and reacting sites of all derivatives (3a–3i)

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Human Epidermal Growth Factor Receptor 2 (HER2) as Surrogate Prognostic Marker in Gastric and Gastro Esophageal Junction Cancer

Background: HER2 is an important biomarker in gastric and gastroesophageal junction tumors. Expression of HER2 status by immunohistochemistry is heterogeneous in various patient populations. This overexpression appears to be an important prognostic factor in gastric cancer and its association with other poor prognostic factors may therefore act as a surrogate marker for poor prognosis in gastric carcinoma. We studied our patient population to look for any such association between HER2 status and various clinicopathological parameters. Objective: To study the association between HER2 status and various clinicopathological parameters. Methods: Patients were prospectively enrolled from August 2013 to March 2015. All relevant patient parameters were recorded. After curative resection, surgical specimens of gastric and gastroesophageal junction adenocarcinoma were analyzed for immunohistochemistry for HER2 by using standard methods. IHC score followed Hofmann's criteria. Statistical analysis of relation between HER2 status and relevant patient and disease characteristics such as gender, age at diagnosis, tumor location, histological type of tumor, stage, and size of tumor, was performed. Results: 106 patients were enrolled into this study. Only 18 (17%) cases had HER2 score of 3+, whereas 5 (4.7%) had equivocal score (2+) and the remaining 84 (78%) tumors tested negative. HER2 status was significantly associated with location of primary tumor, gender, histopathological type of cancer, and size of primary tumor. There was no significant relation between HER2 status and age of patient, depth of invasion, nodal metastasis, or overall stage. Conclusion: Further studies are necessary to determine the significance of HER2 status in upper gastrointestinal cancers especially that the patients need follow up where we can predict the HER2 status as an independent prognostic factor for overall survival

Hypofractionated Radiotherapy as Local Hemostatic Agent in Advanced Cancer

Purpose : Tumor bleeding continues to remain a challenge in an oncological setting, and radiotherapy has been studied as a local hemostatic agent. We studied the role of local radiotherapy in controlling bleeding at our center. Materials and Methods : We reviewed 25 treated cases (cancer urinary bladder: 12, lung cancer: 5, cervical cancer: 4, uterine cancer: 1, rectal cancer: 2, schwanoma: 1) at our center from March 2008 to December 2010. All patients had either an advanced or recurrent disease. Radiotherapy schedule was either 20 Gray in 5 fractions or 15 Gray in 5 fractions and was delivered with Cobalt 60. Results and Conclusion : Of 25 patients, 22 (88%) responded, and there was complete cessation of bleeding. Both 15 Gray and 20 Gray dose schedule had equal efficacy. Treatment was well tolerated without any intermission. Radiotherapy is a safe and effective option in controlling tumor bleeding

Glioblastoma Multiforme: Five-year Experience at a Tertiary Cancer Centre in North India

Background: Glioblastoma Multiforme (GBM) is one of the most common brain tumors. Despite multimodal treatment with surgery and chemoradiotherapy, survival outcome remains bleak. Many patients do not tolerate and complete such aggressive treatment. Our Center is the largest tertiary care referral hospital in the region; we report our findings about 5-year outcome in these patients. Methods: From January 2014 to December 2018, we conducted a retrospective observational study. We included patients with histopathologically proven diagnosis of GBM. Descriptive statistics of patient data was retrieved from patient files at Hospital Based Cancer Registry (HBCR) at our State Cancer Institute (SCI). All the data was recorded and analyzed using appropriate statistical methods. Results: 54 histopathologically proven cases of GBM were enrolled. Most patients were in the fifth and sixth decade of life, with a male to female ratio of 2:1. Headache was the most common presenting symptom in 23 (42.5%) patients followed by seizures in 13 (24%) patients. The average lesion size was 4.7 cm. Gross total excision was done in 12 (22%) patients, near total excision in 8 (15%) patients. 48 (89%) patients received radiation therapy concurrent with temozolomide. 4 (7.4%) patients had complete response with chemoradiotherapy. Median survival was 16 months. Patients who underwent Gross total excision or near total excision had a median survival of 15.9±3.56 months, whereas patients who underwent subtotal excision had a median survival of 8.29±4.14 months. Patients who completed trimodality therapy had better survival. Conclusion: Patients receiving trimodality therapy with gross total excision and adjuvant chemoradiation achieve best survival rates. Advanced age, poor performance score, larger tumor size, deep seated lesions, suboptimal tumor excision, and steroid dependency carry poor prognosis

Early-stage endometrial carcinoma; risk factors for recurrence

Background: Endometrial carcinoma (EC) is the most common gynecological malignancy in developed countries. The overall prognosis is excellent, as most cases are diagnosed at an early stage with low-grade histology, but once the recurrence occurs, the median survival decreases severely. Aims and Objectives: The aim of this study was to identify the risk factors associated with recurrence in early-stage EC and explore their impact on overall survival (OS) after recurrence. Materials and Methods: Records from patients diagnosed with EC were retrospectively reviewed. 220 patients were identified as early-stage, low-risk EC who underwent primary surgical treatment between January 2010 and December 2022, and their baseline characteristics were analyzed. Cox regression analysis was used to identify various factors for tumor recurrence. Survival analysis was done using the Kaplan-Meier method. Results: In a cohort of 220 patients, we observed tumor recurrence in 44 (20%) patients and 34 (15.45%) deaths over a median follow-up of 72 months (range, 12–144 months). Multivariate analysis confirmed two risk factors: myometrial invasion (MMI) of any depth and lymphovascular invasion (LVI) as independent predictors of recurrence. The prognosis was worse for patients with recurrence than for those without. The OS for the recurrent group was 38.6%, compared to 96.0% in the non-recurrent group. In our study, the median time to recurrence was 19 months (confidence interval 18–30) months. Conclusion: The presence of MMI and LVI are important predictors for recurrence in early-stage low-risk EC

Use of Magnetic Nanoparticles as Targeted Therapy: Theranostic Approach to Treat and Diagnose Cancer

The metastasis of cancer epitomizes the diagnostic and therapeutic challenge as a result of cancer heterogeneity. To overcome the uncontrolled growth of the proliferating cells, nanosystems have been developed and have undergone many preclinical trials both in vitro and in vivo and many practices have been further applied clinically on human beings. In practice, magnetic nanoparticles- (MNPs-) based systems following the application of Fe3O4 bound antitumor drug have shown an enhanced therapeutic index in comparison with conventional chemotherapy ensuring the significant decline in nanosystems’ toxicity. A number of improved strategies employing nanoparticle engineering have been in practice for upgrading selectivity of metastatic cells and to have direct access to poorly manageable tumor regions. Targeted nanoparticle therapy paving the way towards tumor biomarkers and tissue specific cancer stages provides effective strategies for nonaccessible tumor regions, thus leading to the tangible modification in the history of cancer world. An infinite number of targets have been exploited for surface receptor specificity to distinct types of nanoparticles and are presently enduring clinical practices both in vitro and in vivo. The aim of this review is to take into view current nanotechnology-based research in cancer imaging for diagnosis and treatment. Several commercially available magnetic nanoparticles-based systems applied as contrast agents for metastatic cancer imaging and treatment via hyperthermia have also been focused on

KRAS Gene Mutations in Relation to Development and Progression of Non-small Cell Lung Carcinoma in Indian Kashmiri Population

Background: The most common molecular alterations observed in non-small cell lung carcinoma (NSCLC) lie in the mutations of KRAS gene. In this study, we have screened prospectively all newly diagnosed patients with NSCLC (n = 70) and blood samples of these patients were collected from Sheri-I-Kashmir Institute of Medical Sciences (SKIMS). Methods: Blood DNA was extracted and amplified by ASO PCR and finally sequenced to detect KRAS mutations. Results: We found 30% prevalence of KRAS mutation rate of NSCLC in the Kashmiri population. The significant association was seen between KRAS gene mutation and histological types of lung cancer. The higher frequency was seen in ADC than SCC and show statistically significant difference (P < 0.01). Also the higher frequency of KRAS (exon 2) mutation was reported in NSCLC patients in advanced stage than the early stages. The difference was statistically significant (P < 0.05). A statistically significant difference was reported between smokers and non-smokers with respect to the KRAS (exon 2) mutation (P < 0.01). The significantly higher frequency of this mutation was reported in NSCLC patients (29.16%) with metastasis (P < 0.03). Conclusion: We finally found that KRAS (exon 2) mutation is a common molecular alteration in NSCLC and occurs most predominantly on codon 12, 13