Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure-Activity Relationships.

Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.

Spontaneous Intragastric Balloon Hyperinflation: Two Cases and Outcomes.

Endoscopic bariatric therapies can provide treatment options for obesity in non-surgical candidates, as a part of combination or serial treatment plans, and for the reduction of obesity-related comorbidities. Several complications of intragastric balloons have been documented, but spontaneous hyperinflation is a risk that has not been well reported previously. We describe two cases of spontaneous intragastric balloon hyperinflation and their outcomes.

Corrigendum: A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth.

[This corrects the article DOI: 10.3389/fphar.2023.1150774.].

An imaging and diagnostic conundrum-the adrenal haemangioma.

The adrenal haemangioma, a rare benign vascular tumour, is increasingly detected through abdominal imaging. Just over 70 surgical cases have been reported since 1955. Their potential large size and overlapping imaging features with adrenocortical carcinoma poses a diagnostic challenge. Adrenalectomy is often needed for a definitive diagnosis due to inconclusive imaging. We report the case of a 61-year-old female presenting with an incidental finding of a right-sided 9.5-cm adrenal mass on imaging. Due to the risk of adrenocortical carcinoma with inconclusive imaging findings, an open right adrenalectomy was performed. The patient was discharged after 6 days with no complications. Post-surgical histopathology confirmed a diagnosis of adrenal haemangioma with a secondary adrenal pseudocyst. The presence of an adrenal incidentaloma with discordant radiological features proves to be a diagnostic conundrum. Therefore, in the setting of contradictory radiology and concerning mass size, we recommend adrenalectomy for definitive diagnosis of an adrenal haemangioma.

A Rare Case of Recurrent Takotsubo Cardiomyopathy Complicated by Thromboemboli.

Takotsubo syndrome (TTS) is a transient ventricular dysfunction with apical ballooning triggered by emotional and/or physical stress. A few risk factors have been observed in patients with recurrent TTS, for example, excessive sympathetic stimuli, medications, stress, and tumors. Clinical features can vary from chest pain to overt hemodynamic instability. Diagnosis requires both electrocardiographic features and invasive imaging such as angiography to rule out other causes of cardiomyopathy prior to diagnosis. In addition, renal infarcts presenting as a complication of TTS are relatively uncommon. In this case report, we discuss the case of a 61-year-old African American woman with a prior history of TTS being managed for abdominal pain who developed a recurrence of the TTS during the hospital course. Prompt diagnosis and management of the condition is crucial to improve outcomes especially in patients with thromboembolic phenomenon or hemodynamic instability. Further large-scale studies are warranted to determine outcomes of patients with recurrent Takotsubo cardiomyopathy with thromboembolic phenomenon.

Sessile serrated polyp detection rates after fecal immunochemical test or multitarget stool DNA test: Systematic review and meta-analysis.

Background and study aims Published studies report a higher adenoma detection rate (ADR) for FIT-DNA as compared with FIT. Data are less replete about the performance of stool-based tests for sessile serrated polyp (SSP) detection. We performed a meta-analysis to evaluate the performance of FIT and FIT-DNA testing for SSP detection rate (SSPDR) in patients undergoing colonoscopy for follow up of positive noninvasive tests. Methods A comprehensive literature search of multiple databases (until September 2022) was performed to identify studies reporting SSPDR in patients with positive FIT or FIT-DNA tests. The outcome was overall colonoscopy detection of any SSPs and advanced serrated polyps (ASP: SSP ≥ 10 mm and/or dysplasia). Results Included were 482,405 patients (52.4% females) with a mean age of 62.3 ± 4.4 years from 23 studies. The pooled SSPDR for all positive stool-based tests was 5.3% and higher for FIT-DNA (15.0%, 95% confidence interval [CI] 8.3-25.7) versus FIT (4.1%, 95% CI 3.0-5.6; P = 0.0002). The overall pooled ASP detection rate was 1.4% (95% CI 0.81-2.3) and higher for FIT-DNA (3.8 %, 95% CI 1.7-8.6) compared with FIT (0.71%, 95% CI 0.36-1.4; P <0.01). SSPDR with FIT-DNA was also significantly higher than FIT when the FIT cutoff was >10 ug/g and in FIT-positive patients in studies conducted in North America ( P <0.05). Conclusions FIT-DNA outperformed FIT in both SSP and ASP detection including FIT with a lower threshold cutoff of >10 ug/g. Further comparative studies are needed to assess the impact of our findings on colorectal cancer reduction.

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents.

DNA polymerase ß (Polß) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polß inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polß was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polß interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Insights into Translational and Biomedical Applications of Hydrogels as Versatile Drug Delivery Systems.

Hydrogels are a network of crosslinked polymers which can hold a huge amount of water in their matrix. These might be soft, flexible, and porous resembling living tissues. The incorporation of different biocompatible materials and nanostructures into the hydrogels has led to emergence of multifunctional hydrogels with advanced properties. There are broad applications of hydrogels such as tissue culture, drug delivery, tissue engineering, implantation, water purification, and dressings. Besides these, it can be utilized in the field of medical surgery, in biosensors, targeted drug delivery, and drug release. Similarly, hyaluronic acid hydrogels have vast applications in biomedicines such as cell delivery, drug delivery, molecule delivery, micropatterning in cellular biology for tissue engineering, diagnosis and screening of diseases, tissue repair and stem cell microencapsulation in case of inflammation, angiogenesis, and other biological developmental processes. The properties like swellability, de-swellability, biodegradability, biocompatibility, and inert nature of the hydrogels in contact with body fluids, blood, and tissues make its tremendous application in the field of modern biomedicines nowadays. Various modifications in hydrogel formulations have widened their therapeutic applicability. These include 3D printing, conjugation, thiolation, multiple anchoring, and reduction. Various hydrogel formulations are also capable of dual drug delivery, dental surgery, medicinal implants, bone diseases, and gene and stem cells delivery. The presented review summarizes the unique properties of hydrogels along with their methods of preparation and significant biomedical applications as well as different types of commercial products available in the market and the regulatory guidance.

A comprehensive evaluation of predictors of obesity in women during the perimenopausal period: A systematic review and narrative synthesis.

INTRODUCTION: Obesity during perimenopausal transition can be attributed to various factors. Identifying these factors is crucial in preventing obesity and developing effective strategies to manage weight during this phase. This review aimed to systematically understand predictors of obesity during menopausal transition. METHODS: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched databases like PubMed, Wiley Online Library, and Cochrane Reviews. Cohort and cross-sectional studies in English language assessing obesity among menopausal women were included. The methodological quality was assessed using Joanna Briggs Checklist for critical appraisal. Risk of Bias (RoB) was generated using Review Manager 5.4.1 (RevMan). Identified predictors were assessed for overall quality of evidence using adopted Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: This review encompassed 42 studies, (21 cross-sectional and 21 cohort) with sample ranging from 164 to 107,243 across studies. Higher parity( ≥ 3 children) emerged as a strong predictor of obesity across seven studies, with good-quality evidence. Lower physical activity was another predictor, supported by eight studies with good-quality evidence. Sociodemographic factors like lower education(<8 years or < than college degree), socioeconomic background, menopausal transition, and older age at menarche showed associations with weight gain, with moderate-quality evidence. Lifestyle factors (high-fat consumption, sedentariness, active smoking status, and psychological difficulties) also showed moderate-quality evidence. CONCLUSION: This review underscores the multifaceted factors associated with obesity during the perimenopausal transition. Identifying these factors will be helpful in prevention and management of obesity among these women.

Histomorphogenesis of sublingual salivary gland of Indian sheep.

The primordial anlage of sublingual gland was first noticed as a solid epithelial bud from oral epithelium at the 24th day of foetal development. The terminal buds were arranged in the form of clusters with undifferentiated epithelial cells and terminated in a bulb-like structure in the 30-day-old sheep foetus. On the 37th day, lumenization and branching of the main cord was noticed. The primary septa were observed from the 55th day onwards which resulted in the formation of lobulation on the 60th day. The capsule formation was initiated by aggregation of mesenchymal tissue on the 63rd day. On the 100th day, terminal tubules differentiated to form secretory end pieces. Tubular portions formed intercalated and striated ducts. Predominantly mucous type of acinar cells was seen from the 110th day onwards with myoepithelial cells. The number of lobules increased with increase in parenchyma from 130th day onwards. Micrometrical studies revealed that the mean diameter of acini, intercalated, striated and large ducts was increased with advancement of age and significant differences were observed between groups. Localization of acidic and neutral mucopolysaccharides were observed in mucous and goblet cells. Fine lipid droplets were observed in intralobular and interlobular connective tissue however, phospholipids were observed in cell membrane of acini and ducts. The current investigation provides microstructural standards for the organogenesis of the sublingual gland of miniature sheep and can lay the foundation for further studies in the morphological investigation of salivary gland development.

Development of a specific and potent IGF2BP1 inhibitor: A promising therapeutic agent for IGF2BP1-expressing cancers.

IGF2BP1 is a protein that controls the stability, localization, and translation of various mRNA targets. Poor clinical outcomes in numerous cancer types have been associated with its overexpression. As it has been demonstrated to impede tumor growth and metastasis in animal models, inhibiting IGF2BP1 function is a promising strategy for combating cancer. A lead chemical, 7773, which specifically decreased IGF2BP1 RNA binding and cellular activities, was previously identified in a high-throughput screen for effective IGF2BP1 inhibitors. Additional optimization of 7773 described in this manuscript led to the discovery of six compounds that performed equally well or better than 7773. In cell lines with high levels of endogenous IGF2BP1, one of 7773 derivatives, AVJ16, was found to be most efficient at preventing cell migration. Further, AVJ16 was found to be IGF2BP1-specific because it had no effect on cell lines that expressed little or no IGF2BP1 protein. The direct binding of AVJ16 to IGF2BP1 was validated by binding tests, with a 12-fold increase in binding efficiency over the lead compound. AVJ16 was shown to bind to a hydrophobic region at the protein's KH34 di-domain interface between the KH3 and KH4 domains. Overall, the findings imply that AVJ16 is a potent and specific inhibitor of IGF2BP1 activity.

A Rare Case of Extra-Pulmonary Sarcoidosis With Only Initial Presentation of Hypercalcemia.

Sarcoidosis is a systemic disorder characterized by the aberrant development of granulomatous inflammation within various organs in the body. In over 90% of cases, sarcoidosis typically manifests initially in the intra-thoracic region, characterized by pulmonary involvement or mediastinal lymphadenopathy. It is rare for sarcoidosis to manifest exclusively as extra-thoracic involvement and even more rarely for hypercalcemia to be the only initial sign. We present a case of a 70-year-old female with hypercalcemia and elevated 1,25-dihydroxyvitamin D3 (1,25(OH)2 D) which raised the suspicion of a granulomatous disease. Granulomatous diseases increase levels of 1,25(OH)2 D via the abnormal expression of 1 alpha-hydroxylase enzyme; therefore, these conditions should be considered in the differential diagnosis when encountered with hypercalcemia. PET-CT showed increased FDG uptake in the reticuloendothelial system. An easily accessible inguinal lymph node biopsy was performed which revealed non-necrotizing granulomatous inflammation. Other causes of non-necrotizing granulomatous diseases, cancer, and lymphoma were ruled out, leading to sarcoidosis being considered as a possible diagnosis. When diagnosing sarcoidosis, other potential causes of granulomatous inflammation need to be ruled out definitively via laboratory findings, imaging, and tissue histopathology before initiation of treatment with steroids. Treatment with glucocorticoids remains the mainstay therapy of 1,25(OH)2 D-mediated hypercalcemia associated with sarcoidosis. The patient was accordingly treated with prednisone which led to the normalization of calcium and 1,25(OH)2 D levels within three weeks. Here, we discuss the clinical features and investigations of extra-pulmonary sarcoidosis for early diagnosis and management.

The Utility of Galactomannan and Polymerase Chain Reaction Assays in Bronchoalveolar Lavage for Diagnosis of Chronic Pulmonary Aspergillosis.

The diagnosis of chronic pulmonary aspergillosis (CPA) is established by combined clinic-radio-microbiological criteria. Out of the different microbiological criteria, a positive serology for Aspergillus-specific IgG levels is the cornerstone of diagnosis. Alternatively, other microbiological evidence are sometimes sought viz., positive Aspergillus antigen (broncho-alveolar lavage fluid, i.e., BALF galactomannan ≥ 1.0), histopathological demonstration of the fungi following lung biopsy or resection, demonstration of hyaline septate hyphae in direct microscopy resembling Aspergillus spp. or its growth on a respiratory specimen. However, the exact roles of BALF- GM and the newer BALF-PCR have not been confirmed by studies till date. This study enrolled 210 patients with suspected CPA. Of the participants, 88 patients met the criteria for CPA, whereas 122 patients had an alternative diagnosis. The sensitivity-specificity of AsperGenius® PCR and "in-house" PCR were 52.27(36.69-67.54) %-33.78 (23.19-45.72) % and 36.36 (22.41-52.23) %-39.19 (28.04-51.23) % respectively. The sensitivity/specificity of BALF (> 1.0) and serum galactomannan (> 1.0) were 46.55% (33.34-60.13)/64.08% (54.03-73.3) and 29.82% (22.05-37.6)/86.84% (81.1-92.59) respectively. The optimal cut-off values for BALF-Galactomannan and serum galactomannan in diagnosing CPA were found to be 0.69 (sensitivity: 64%; specificity: 53%) and 0.458 (sensitivity: 67%; specificity: 64%) respectively. This results of this study suggests that Aspergillus PCR from BAL may not be a good "rule-in" test for diagnosing CPA. While the performances of GM in BAL and serum may be better than PCR, it should be best used in conjunction with other clinical, radiological, and other microbiological characteristics.

A Compiled Update on Nutrition, Phytochemicals, Processing Effects, Analytical Testing and Health Effects of Chenopodium album: A Non-Conventional Edible Plant (NCEP).

Bathua (Chenopodium album) is a rich source of extensive-ranging nutrients, including bio-active carbohydrates, flavonoids and phenolics, minerals, and vitamins that translate to countless health benefits such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antioxidant activity. Ascaridole, an important phytoconstituent present in aerial parts of the plant, contributes to its anthelmintic property. Even with vast historical use and significant health benefits, its renown has not spread, and utilization has significantly decreased in recent decades. Gradually, the plant has become known under the name of Non-conventional edible plant (NCEP). This compilation is prepared to bring out the plant under the spotlight for further research by foregrounding previous studies on the plant. Scientific research databases, including PubMed, Google Scholar, Scopus, SpringerLink, ScienceDirect, and Wiley Online, were used to fetch data on C. album. This review offers over up-to-date knowledge on nutritious values, phytochemical composition, volatile compounds, as well as health benefits of C. album. The ethnobotanical and ethnomedicinal uses of the plant in India and other parts of the world are deliberately discussed. Scrutinizing the reported literature on C. album reveals its powerful nutrient composition advantageous in the development of food products. The impact of various cooking and processing methods on the nutritional profile and bioavailability are discussed. The future perspectives with regards to the potential for food and nutraceutical products are critically addressed. This review proves the necessity of breakthrough research to investigate the pharmacology and safety of phytochemicals and nutraceutical development studies on the C. album.

Long-term recurrence after endoscopic versus surgical ampullectomy of sporadic ampullary adenomas: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Ampullary adenomas are treated both surgically and endoscopically, however, data comparing both techniques are lacking. We aimed to compare long-term recurrence of benign sporadic adenomas after endoscopic (EA) and surgical ampullectomy (SA). METHODS: A comprehensive literature search of multiple databases (until December 29, 2020) was performed to identify studies reporting outcomes of EA or SA of benign sporadic ampullary adenomas. The outcome was recurrence rate at 1 year, 2-year, 3 year and 5 years after EA and SA. RESULTS: A total of 39 studies with 1753 patients (1468 EA [age 61.1 ± 4.0 years, size 16.1 ± 4.0 mm], 285 SA [mean age 61.6 ± 4.48 years, size 22.7 ± 5.4 mm]) were included in the analysis. At year 1, pooled recurrence rate of EA was 13.0% (95% confidence interval [CI] 10.5-15.9], I2 = 31%) as compared to SA 14.1% (95% CI 9.5-20.3 I2 = 15.8%) (p = 0.82). Two (12.5%, [95% CI, 8.9-17.2] vs. 14.3 [95% CI, 9.1-21.6], p = 0.63), three (13.3%, [95% CI, 7.3-21.6] vs. 12.9 [95% CI, 7.3-21.6], p = 0.94) and 5 years (15.7%, [95% CI, 7.8-29.1] vs. 17.6% [95% CI, 6.2-40.8], p = 0.85) recurrence rate were comparable after EA and SA. On meta-regression, age, size of lesion or enbloc and complete resection were not significant predictors of recurrence. CONCLUSION: EA and SA of sporadic adenomas have similar recurrence rates at 1, 2, 3 and 5 years of follow up.

The Effect of Obesity on Gastrointestinal Disease.

Obesity exerts both direct and indirect effects on gastrointestinal function. From physical effects of central adiposity on intragastric pressure resulting in higher incidence of reflux to dyslipidemia and effects on gallstone disease, the gastrointestinal manifestations of obesity are wide-ranging. Of particular emphasis is the identification and management of non-alcoholic fatty liver disease including non-invasive assessment and lifestyle and pharmacologic interventions for patients with non-alcoholic steatohepatitis. Additional focus is on the impact of obesity and western diet on intestinal disorders and colorectal cancer. Bariatric interventions involving the gastrointestinal tract are also discussed.

Corrigendum: A small molecule inhibitor of Notch1 modulates stemness and suppresses breast cancer cell growth.

[This corrects the article DOI: 10.3389/fphar.2023.1150774.].

Synchronous Pancreatic Masses.

Any mass lesion in the pancreas usually raises the possibility of undiagnosed pancreatic cancer. With the advancement of imaging modalities, we are seeing an increasing number of incidental findings, some of which may be clinically significant. When dealing with incidental pancreatic findings, it is critical to keep a broad differential in mind in addition to ruling out pancreatic malignancy. We present 3 rare cases of patients with 2 or more synchronous solid masses in the pancreas caused by pancreatic cancer, type 1 autoimmune pancreatitis, and sarcoidosis.

Endoscopic versus surgical management for colonic volvulus hospitalizations in the United States.

BACKGROUND/AIMS: Colonic volvulus (CV), a common cause of bowel obstruction, often requires intervention. We aimed to identify hospitalization trends and CV outcomes in the United States. METHODS: We used the National Inpatient Sample to identify all adult CV hospitalizations in the United States from 2007 to 2017. Patient demographics, comorbidities, and inpatient outcomes were highlighted. Outcomes of endoscopic and surgical management were compared. RESULTS: From 2007 to 2017, there were 220,666 CV hospitalizations. CV-related hospitalizations increased from 17,888 in 2007 to 21,715 in 2017 (p=0.001). However, inpatient mortality decreased from 7.6% in 2007 to 6.2% in 2017 (p<0.001). Of all CV-related hospitalizations, 13,745 underwent endoscopic intervention, and 77,157 underwent surgery. Although the endoscopic cohort had patients with a higher Charlson comorbidity index, we noted lower inpatient mortality (6.1% vs. 7.0%, p<0.001), mean length of stay (8.3 vs. 11.8 days, p<0.001), and mean total healthcare charge ($68,126 vs. $106,703, p<0.001) compared to the surgical cohort. Male sex, increased Charlson comorbidity index scores, acute kidney injury, and malnutrition were associated with higher odds of inpatient mortality in patients with CV who underwent endoscopic management. CONCLUSION: Endoscopic intervention has lower inpatient mortality and is an excellent alternative to surgery for appropriately selected CV hospitalizations.