Unveiling the therapeutic potential of plant steroid peimine: A study on apoptotic induction in MRMT-1 cell line-induced breast cancer in rats.

BACKGROUND: Breast cancer stands as a leading contributor to global cancer-related mortality. Progressing Research and Medical Innovations Elevate Treatment Choices and Results for Breast Cancer. Among these, Peimine, a natural steroid inherent in plants, notably within the Fritillaria species, demonstrates the capability to trigger apoptosis in breast cancer cells through the mitochondrial membrane permeation pathway. Nevertheless, its impact on an appropriate cancer model remains an area necessitating further exploration. AIM: This study explored the in vivo anticancer effects of peimine on MRMT-1 Cell-line induced breast cancer in rats. METHOD: Cancer was induced by the administration of MRMT-1 (6 x 106 cells) cells in the mammary pads of SD rats. The daily drug treatmentcommenced on day 14 and continued till 39 days. Peimine was administered in two doses (0.24 mg/kg and 0.48 mg/kg p.o) to examine its efficacy in curing breast cancer while tamoxifen was used as standard. RESULTS: A reduction in tumour size was observed in the peimine-treated groups. Peimine can correct the changed blood cell count in addition to its anti-tumour activity. In peimine-treated rats, imbalanced immune marker IgE, serum oxidative marker, and tissue apoptotic markers like cytochrome c and calcium level were shown to be restored significantly. CONCLUSION: Our findings imply that quinine has beneficial effects as an anti-neoplastic medication for breast cancer, most likely through its apoptotic activity. More research is necessary to thoroughly understand their mechanisms of action, ideal dose, and potential side effects.

Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

Radiative cooling and indoor light management enabled by a transparent and self-cleaning polymer-based metamaterial.

Transparent roofs and walls offer a compelling solution for harnessing natural light. However, traditional glass roofs and walls face challenges such as glare, privacy concerns, and overheating issues. In this study, we present a polymer-based micro-photonic multi-functional metamaterial. The metamaterial diffuses 73% of incident sunlight, creating a more comfortable and private indoor environment. The visible spectral transmittance of the metamaterial (95%) surpasses that of traditional glass (91%). Furthermore, the metamaterial is estimated to enhance photosynthesis efficiency by ~9% compared to glass roofs. With a high emissivity (~0.98) close to that of a mid-infrared black body, the metamaterial is estimated to have a cooling capacity of ~97 W/m2 at ambient temperature. The metamaterial was about 6 °C cooler than the ambient temperature in humid Karlsruhe. The metamaterial exhibits superhydrophobic performance with a contact angle of 152°, significantly higher than that of glass (26°), thus potentially having excellent self-cleaning properties.

Outcomes of Conversion Surgery for Patients With Low-Risk Papillary Thyroid Carcinoma.

Importance: The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined. Objective: To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma. Design, Setting, and Participants: In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score-matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States. Exposures: Surgery. Main Outcomes and Measures: Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). Results: Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group. Conclusions and Relevance: In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.

Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor.

RyR1 is an intracellular Ca2+ channel important in excitable cells such as neurons and muscle fibers. Ca2+ activates it at low concentrations and inhibits it at high concentrations. Mg2+ is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg2+-mediated inhibition, the molecular-level mechanisms remain unclear. In this work we determined two cryo-EM structures of RyR1 with Mg2+ up to 2.8 Å resolution, identifying multiple Mg2+ binding sites. Mg2+ inhibits at the known Ca2+ activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg2+ inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg2+ inhibition is overcome during excitation.

Exploring the effects of vasoactive constituents in large cardamom: implications for the anti-hypertensive effect via eNOS coupling pathway - an in-vitro study in rat endothelial cells.

Endothelial dysfunction, linked to reduced eNOS expression and nitric oxide (NO) availability, contributes to cardiovascular diseases (CVDs). Large cardamom exhibits antihypertensive effects by augmenting NO levels and antioxidant activity. To decipher its mechanisms, selected constituents were docked with eNOS-associated target genes such as GTP cyclohydrolase I (GTPCH-1) and (dihydrofolate reductase [DHFR]). Endothelial damage induced by L-NAME and fructose was countered by assessing nitric oxide metabolites (NOx), tetrahydrobipterin (BH4 levels), GCH-I expression and super oxide dismutase (SOD) activity after constituent incubation. Cyanidin-3-O-glucoside and petunidin-3-O-glucoside notably restored impaired vascular markers in both models. These phytoconstituents are likely to activate GCH-BH4-eNOS pathways, upregulating SOD and NO expression, maintaining endothelial integrity. Large cardamom's antihypertensive effects may stem from these components, synergistically enhancing endothelial NO release via the eNOS pathway.

Recurrent Laryngeal Nerve Intraoperative Neuromonitoring Indications in Non-Thyroid and Non-Parathyroid Surgery.

Introperative nerve monitoring (IONM) of the recurrent laryngeal nerve (RLN) is a well-established technique to aid in thyroid/parathyroid surgery. However, there is little evidence to support its use in non-thyroid or non-parathyroid surgery. The aim of this paper was to review the current evidence regarding the use of IONM in non-thyroid/non-parathyroid surgery in the head and neck and thorax. A literature search was performed from their inception up to January 2024, including the term "recurrent laryngeal nerve monitoring". IONM in non-thyroid/non-parathyroid surgery has mainly been previously described in oesophageal surgery and in tracheal resections. However, there is little published evidence on the role of IONM with other resections in the vicinity of the RLN. Current evidence is low-level for the use of RLN IONM in non-thyroid/non-parathyroid surgery. However, clinicians should consider its use in surgery for pathologies where the RLN is exposed and could be injured.

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Metastatic Tonsil Squamous Cell Carcinoma: An Important Consideration in the Differential Diagnosis of Malignant Basaloid Neoplasms in the Skin: Case Report and Review of the Literature.

ABSTRACT: Malignant basaloid neoplasms of the skin are frequent, and their accurate diagnosis holds paramount importance for treatment and prognosis. However, these neoplasms can present diagnostic challenges because of their extensive differential diagnosis, which encompasses cutaneous metastasis among many other possibilities. We present a case of a 74-year-old man with a history of p16-positive palatine tonsil squamous cell carcinoma (SCC) treated with surgery and adjuvant radiation with no prior evidence of recurrence who presented to the dermatologist with 2 chin papules. The initial histopathologic evaluation of these lesions showed poorly differentiated malignant basaloid neoplasms. Subsequently, these biopsies were compared with the previous biopsies from his tonsil and lymph node, which showed similar findings including positive p16 staining and positive molecular testing for human papillomavirus-16, confirming the diagnosis of cutaneous metastasis from his previously diagnosed human papillomavirus-related tonsil SCC. Additional imaging studies found metastases to internal organs including the brain, and he was started on chemotherapy, immunotherapy, and radiation therapy. Cutaneous metastases from tonsil SCC are exceedingly rare, and only 5 cases have been described. Furthermore, this is the first case confirming the presence of high-risk human papillomavirus by molecular studies within the cutaneous metastases. The presented case underscores the importance of recognizing this unusual manifestation of tonsil SCC metastatic to the skin along with a good clinical patient history, ensuring accurate and prompt diagnosis and treatment of this condition.

Current evidences in poorly differentiated thyroid carcinoma: a systematic review and subsection meta-analysis for clinical decision making.

BACKGROUND: Poorly differentiated thyroid carcinoma (PDTC) is a distinct entity with intermediate prognosis between indolent follicular thyroid cancers and anaplastic carcinoma. The management guidelines are not standardized for these cancers due its low prevalence and limited available literature. Therefore, we did this systematic review with emphasis on current evidence on diagnosis, imaging, molecular markers, and management of these carcinomas. MATERIALS AND METHODS: We searched four databases, PubMed, Medline, EMBASE, and Emcare to identify studies published till October 2023. All studies reporting diagnostic tests, imaging, molecular marker expression and management of PDTC were included in the review. The meta-analysis was conducted on expression of molecular markers in these cancers following recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Random-effects meta-analysis was used to calculate pooled estimated prevalence with 95% confidence intervals. Based on the inclusion criteria, 62 articles were selected to be incorporated for the review. Differences in pathological diagnostic criteria of PDTC was noted in literature which was addressed in WHO 2022 diagnostic terminologies with expansion of the definition. Surgical management is uniformly recommended for early stage PDTC. However, literature is divided and anecdotal for recommendations on radioactive iodine (RAI), extent of neck dissection and adjuvant treatment in PDTC. Evidence for Next Generation Sequencing (NGS), novel theragnostic approaches, immunotherapy targets are evolving. Based on the subset analysis for expression of molecular markers, we found the most common markers expressed were TERT (41%), BRAF (28%) and P 53 (25%). CONCLUSION: Poorly differentiated thyroid carcinomas have a high case fatality rate (up to 31%). Eighty-five % of the patients who succumb to the disease have distant metastasis. Even though under-represented in literature, evidence-based management of these aggressive tumors can help personalize the treatment for optimal outcomes.

Papillary thyroid carcinoma tall cell subtype (PTC-TC) and high-grade differentiated thyroid carcinoma tall cell phenotype (HGDTC-TC) have different clinical behaviour: a retrospective study of 1456 patients.

AIMS: Papillary thyroid carcinoma, tall cell subtype (PTC-TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high-grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC-TC). METHODS AND RESULTS: We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC-TC and HGDTC-TC. HGDTC-TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC-TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis-free survival (DMFS; P < 0.001). The 10-year DSS was 72 and 99%, the 10-year LRDFS was 61 and 92% and the 10-year DMFS was 53 and 97%, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification (HGDTC-TC versus PTC-TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. CONCLUSIONS: Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC-TC versus 34% in PTC-TC) and incurs a significantly worse prognosis. HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas.

Exploration of potential immune mechanisms in cervical dystonia.

BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Chronic SIV-Induced neuroinflammation disrupts CCR7+ CD4+ T cell immunosurveillance in the rhesus macaque brain.

CD4+ T cells survey and maintain immune homeostasis in the brain, yet their differentiation states and functional capabilities remain unclear. Our approach, combining single-cell transcriptomic analysis, ATAC-Seq, spatial transcriptomics, and flow cytometry, revealed a distinct subset of CCR7+ CD4+ T cells resembling lymph node central memory (TCM) cells. We observed chromatin accessibility at the CCR7, CD28, and BCL-6 loci, defining molecular features of TCM. Brain CCR7+ CD4+ T cells exhibited recall proliferation and interleukin-2 production ex vivo, showcasing their functional competence. We identified the skull bone marrow as a local niche for these cells alongside CNS border tissues. Sequestering TCM cells in lymph nodes using FTY720 led to reduced CCR7+ CD4+ T cell frequencies in the cerebrospinal fluid, accompanied by increased monocyte levels and soluble markers indicating immune activation. In macaques chronically infected with SIVCL757 and experiencing viral rebound due to cessation of antiretroviral therapy, a decrease in brain CCR7+ CD4+ T cells was observed, along with increased microglial activation and initiation of neurodegenerative pathways. Our findings highlight a role for CCR7+ CD4+ T cells in CNS immune surveillance, and their decline during chronic SIV highlights their responsiveness to neuroinflammation.

Cabergoline as a Novel Strategy for Post-Pregnancy Breast Cancer Prevention in Mice and Human.

Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer limited efficacy and considerable side effects. Here, we report that cabergoline, a dopaminergic agonist, reduces the risk of breast cancer post-pregnancy in a Brca1/P53-deficient mouse model, with implications for human breast cancer prevention. We show that a single dose of cabergoline administered post-pregnancy significantly delayed the onset and reduced the incidence of breast cancer in Brca1/P53-deficient mice. Histological analysis revealed a notable acceleration in post-lactational involution over the short term, characterized by increased apoptosis and altered gene expression related to ion transport. Over the long term, histological changes in the mammary gland included a reduction in the ductal component, decreased epithelial proliferation, and a lower presence of recombinant Brca1/P53 target cells, which are precursors of tumors. These changes serve as indicators of reduced breast cancer susceptibility. Additionally, RNA sequencing identified gene expression alterations associated with decreased proliferation and mammary gland branching. Our findings highlight a mechanism wherein cabergoline enhances the protective effect of pregnancy against breast cancer by potentiating postlactational involution. Notably, a retrospective cohort study in women demonstrated a markedly lower incidence of post-pregnancy breast cancer in those treated with cabergoline compared to a control group. Our work underscores the importance of enhancing postlactational involution as a strategy for breast cancer prevention, and identifies cabergoline as a promising, low-risk option in breast cancer chemoprevention. This strategy has the potential to revolutionize breast cancer prevention approaches, particularly for women at increased risk due to genetic factors or delayed childbirth, and has wider implications beyond hereditary breast cancer cases.

Active surveillance for micropapillary thyroid carcinoma: a clinical review.

With the rapid rise in the incidence of micropapillary carcinoma, there is increasing concern about its overdiagnosis and overtreatment. There is considerable interest in managing patients with micropapillary carcinoma with active surveillance or deferred intervention. Various institutions around the world are practicing active surveillance. The major question remains as to who the ideal candidates are and how best to monitor these patients. This clinical review will discuss the ideal, appropriate, and inappropriate patients for active surveillance. It will also discuss the follow-up strategy for these patients and some of the adverse clinical features that will be used to decide against active surveillance. There are uncertainties as to who should be offered active surveillance. Various studies have shown approximately 10% of the patients switching to surgery primarily related to fear factor rather than increase in the tumor size or lymph node metastasis. The results of immediate surgery do raise issues related to complications of thyroid surgery and quality of life. The most ideal candidate would be patients with a tumor below 1 cm, intrathyroidal. For the patient who is a minimalist, the follow up strategy includes, ultrasound every 6 months for the first 1 or 2 years, and then every year after that. If there is a substantial change in the tumor volume or nodal metastasis, surgery should be considered, which happens in less than 10 percent of patients according to many studies. Based on existing literature and clinical experience, it appears that active surveillance is an appropriate strategy for monitoring micropapillary carcinoma.

An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

BACKGROUND: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging. OBJECTIVE: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm. METHODS: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing. Outcome measures included multiple scales rated by clinicians or participants, digital video, and a wearable sensor. RESULTS: Dipraglurant was well tolerated, with no obvious impact on any of the measurement outcomes. Power analyses suggested fewer subjects would be required for studies using a within-subject versus independent group design, especially for certain measures. Some outcome measures appeared more suitable than others. CONCLUSION: Although dipraglurant appeared well tolerated, it did not produce a trend for clinical benefit. The results provide valuable information for planning further trials in blepharospasm. © 2024 International Parkinson and Movement Disorder Society.

NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Review on advancements of pyranopyrazole: synthetic routes and their medicinal applications.

Pyranopyrazoles are among the most distinguished, biologically potent, and exciting scaffolds in medicinal chemistry and drug discovery. Synthesis and design of pyranopyrazoles using functional modifications via multicomponent reactions (MCRs) are thoroughly found in synthetic protocols by forming new C-C, C-N, and C-O bonds. This review aims to focus on the biological importance of pyranopyrazoles as well as on a diverse synthetic approach for their synthesis using various catalytic systems such as acid-catalyzed, base-catalyzed, ionic liquids and green media-catalyzed, nano-particle-catalyzed, metal oxide-supported catalysts, and silica-supported catalysts. In this review, we have summarized data on the advancements in synthesizing pyranopyrazole from the last two decades to the mid-2023 and research papers describing the importance of these scaffolds. This review will be significant for synthetic organic chemists and researchers working in organic chemistry.