A spectral domain optical coherence tomography (SD-OCT) study of intraretinal hyperreflective foci and its relationship with visual acuity and grades of retinopathy among patients of diabetes mellitus in Indian population.

Background: Hyperreflective foci (HRF) are biomarkers in detection of diabetic retinopathy (DR). Presence of HRF on spectral domain optical coherence tomography (SD-OCT) can give a correlation with visual acuity change and grades of DR. Purpose of this study is to determine the presence, location, and role of HRF in the retina of DM patients with and without retinopathy. Methods: A total of 192 eyes of patients suffering from type II DM were evaluated. Patients were divided into 2 groups, with Group A having diabetes without retinopathy (20 patients) and group B (76 patients) having diabetes and various grades of retinopathy. SD-OCT was performed in all patients, passing through the center of fovea. On OCT, presence and absence of HRF were noted. Characteristics of the hyper-reflective spots were evaluated: location, shape, size, back shadowing and association with central macular thickness (CMT), visual acuity, and grades of retinopathy. Results: HRF were present in 169 eyes (88%) out of 192 eyes. The shape and location of HRF tend to change with disease progression. HRF were significantly associated with increasing grades of retinopathy (χ2 = 57.586, p < 0.01) Association of macular edema was significant with both retinopathy (χ2 = 8.895, p < 0.05) and HRF (χ2 = 34.720, p < 0.01). Association of best-corrected visual acuity with HRF (χ2 = 21.232, p < 0.01), macular edema (χ2 = 86.960, p < 0.01), and CMT (χ2 = 47.959, p< 0 .01) was significant. Conclusion: HRF is a great indicator for early diagnosis of subclinical retinopathy and can be used to monitor the progression of disease and development of macular edema. Significant difference is present in HRF distribution and morphology.

Cross-talk between the microbiome and chronic inflammation in esophageal cancer: potential driver of oncogenesis.

Esophageal cancer (EC) is frequently considered a lethal malignancy and is often identified at a later stage. It is one of the major causes of cancer-related deaths globally. The conventional treatment methods like chemotherapy, radiotherapy, and surgery offer limited efficacy and poor clinical outcome with a less than 25% 5-year survival rate. The poor prognosis of EC persists despite the growth in the development of diagnostic and therapeutic modalities to treat EC. This underlines the need to elucidate the complex molecular mechanisms that drive esophageal oncogenesis. Apart from the role of the tumor microenvironment and its structural and cellular components in tumorigenesis, mounting evidence points towards the involvement of the esophageal microbiome, inflammation, and their cross-talk in promoting esophageal cancer. The current review summarizes recent research that delineates the underlying molecular mechanisms by which the microbiota and inflammation promote the pathophysiology of esophageal cancer, thus unraveling targets for potential therapeutic intervention.

Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.

BACKGROUND: Osteosarcoma is a type of bone cancer that predominantly affects young individuals, including children and adolescents. The disease progresses through heterogeneous genetic alterations, and patients often develop pulmonary metastases even after the primary tumors have been surgically removed. Ubiquitin-specific peptidases (USPs) regulate several critical cellular processes, such as cell cycle progression, transcriptional activation, and signal transduction. Various studies have revealed the significance of USP37 in the regulation of replication stress and oncogenesis. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was analyzed to investigate USP37 expression. RNA sequencing was utilized to assess the impact of USP37 overexpression and depletion on gene expression in osteosarcoma cells. Various molecular assays, including colony formation, immunofluorescence, immunoprecipitation, and DNA replication restart, were employed to examine the physical interaction between USP37 and PCNA, as well as its physiological effects in osteosarcoma cells. Additionally, molecular docking studies were conducted to gain insight into the nature of the interaction between USP37 and PCNA. Furthermore, immunohistochemistry was performed on archived tissue blocks from osteosarcoma patients to establish a correlation between USP37 and PCNA expression. RESULTS: Analysis of the TCGA database revealed that increased expression of USP37 was linked to decreased progression-free survival (PFS) in osteosarcoma patients. Next-generation sequencing analysis of osteosarcoma cells demonstrated that overexpression or knockdown of USP37 led to the expression of different sets of genes. USP37 overexpression provided a survival advantage, while its depletion heightened sensitivity to replication stress in osteosarcoma cells. USP37 was found to physically interact with PCNA, and molecular docking studies indicated that the interaction occurs through unique residues. In response to genotoxic stress, cells that overexpressed USP37 resolved DNA damage foci more quickly than control cells or cells in which USP37 was depleted. The expression of USP37 varied in archived osteosarcoma tissues, with intermediate expression seen in 52% of cases in the cohort examined. CONCLUSION: The results of this investigation propose that USP37 plays a vital role in promoting replication stress tolerance in osteosarcoma cells. The interaction between USP37 and PCNA is involved in the regulation of replication stress, and disrupting it could potentially trigger synthetic lethality in osteosarcoma. This study has expanded our knowledge of the mechanism through which USP37 regulates replication stress, and its potential as a therapeutic target in osteosarcoma merits additional exploration.

Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments.

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Integration of CRISPR/Cas9 with artificial intelligence for improved cancer therapeutics.

Gene editing has great potential in treating diseases caused by well-characterized molecular alterations. The introduction of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based gene-editing tools has substantially improved the precision and efficiency of gene editing. The CRISPR/Cas9 system offers several advantages over the existing gene-editing approaches, such as its ability to target practically any genomic sequence, enabling the rapid development and deployment of novel CRISPR-mediated knock-out/knock-in methods. CRISPR/Cas9 has been widely used to develop cancer models, validate essential genes as druggable targets, study drug-resistance mechanisms, explore gene non-coding areas, and develop biomarkers. CRISPR gene editing can create more-effective chimeric antigen receptor (CAR)-T cells that are durable, cost-effective, and more readily available. However, further research is needed to define the CRISPR/Cas9 system's pros and cons, establish best practices, and determine social and ethical implications. This review summarizes recent CRISPR/Cas9 developments, particularly in cancer research and immunotherapy, and the potential of CRISPR/Cas9-based screening in developing cancer precision medicine and engineering models for targeted cancer therapy, highlighting the existing challenges and future directions. Lastly, we highlight the role of artificial intelligence in refining the CRISPR system's on-target and off-target effects, a critical factor for the broader application in cancer therapeutics.

Pazopanib based oral metronomic therapy for platinum resistant/refractory epithelial ovarian cancer: A phase II, open label, randomized, controlled trial.

BACKGROUND: Treatment of patients with platinum resistant/refractory epithelial ovarian cancer (EOC) is an unmet need. We evaluated the role of oral metronomic therapy in this setting. PATIENTS AND METHODS: Between October 2017 and September 2019 seventy five patients with platinum resistant/refractory EOC were enrolled. Patients received oral etoposide (50 mg, day 1 to 14, cyclophosphamide 50 mg, day 1 to 28, every 4 weeks (Arm A, n = 38). Patients in Arm- B (n = 37) received Pazopanib (400 mg once daily) in addition to etoposide and cyclophosphamide. Quality of life (QoL) was evaluated using the EORTC questionnaire. Serum VEGF and PDGF were estimated at baseline, after 3rd and 6th cycle. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and QoL. RESULTS: Patients characteristics were well matched. Median PFS was higher in arm B, 5.1 months (95% CI 3.13 to10.33) compared to 3.4 months (95% CI 3.0 to 6.53) in arm A, p = 0.045. Median OS has 'not reached' in Arm B compared to 11.2 months (95% CI, 5.66 - not reached) in arm A, p = 0.032. Therapy was tolerated well; oral mucositis (p = 0.36) and fatigue (p = 0.08) being more in arm B. QoL assessment revealed modest improvement in 'symptom scales' in Arm B. Serum VEGF and PDGF levels decreased with therapy in both arms (Arm A-p < 0.0001, Arm B-p < 0.016). CONCLUSION: Addition of pazopanib to etoposide and cyclophosphamide could be a novel oral combination for metronomic therapy for platinum resistant/refractory EOC. TRIAL REGISTRATION: CTRI/2017/10/010219.

Outcome of pediatric retinal detachment using high-density silicone oil.

BACKGROUND: The high-density silicone oil (Densiron), a mixture of F6H8 with silicone oil, has been used in the management of retinal detachment (RD) complicated by the presence of proliferative vitreoretinopathy (PVR) with varying rate of anatomical success and visual outcomes. METHODS: We conducted a prospective interventional case series of 22 eyes in 22 children less than 18 years diagnosed with complicated retinal detachment complicated by the presence of PVR in inferior quadrant. RESULTS: The mean age of the patients was 8.45 ± 3.36 years. There were 14 male and 8 female children. Five patients presented with total RD, 5 had subtotal RD and remaining 10 with inferior retinal detachment. There were 8 children with PVR C1, 13 with PVR C2, 3 with PVR C3. All patient's had macula off RD at presentation. The anatomical success in the form of attached retina was achieved in 21 (95.45%) eyes. Standard three-port pars plana vitrectomy without scleral buckling under general anesthesia was surgical technique employed in all cases. CONCLUSION: Densiron can be an important tamponade agent in pediatric retinal detachment complicated by PVR with increased success rate of retinal re-attachment.

Genetic characterization and phylogenetic analysis of Sarcocystis suihominis infecting domestic pigs (Sus scrofa) in India.

A total of 57 tissue samples of domestic pigs (Sus scrofa) were collected from the meat outlets of five north Indian states and examined for sarcocystosis by histological and molecular methods. The genomic DNA extracted from five representative positive isolates was subjected to PCR amplification of the partial 18S rRNA gene followed by cloning and sequencing. Sequence analysis of the newly generated Indian isolates recorded 96.9-100.0% identity with published sequences of Sarcocystis suihominis. Two new haplotypes that have not been previously described manifested 99.5-100.0% nucleotide homology within themselves. In the phylogenetic analysis, Indian isolates of S. suihominis grouped together with S. suihominis originating from Italy, and they collectively formed a sister clade with Sarcocystis miescheriana within a clade containing various Sarcocystis spp. of ruminants having felids as final hosts. At the same time, this clade separated from a sister clade containing Sarcocystis spp. of bovid or cervid ruminants using canids as known or surmised definitive host. The current study established the phylogenetic relationship of Indian isolates of S. suihominis with various Sarcocystis spp. as well as with other taxa of Sarcocystidae family based on 18S rRNA gene for the first time.

Adequate Reporting of Dental Diagnostic Accuracy Studies is Lacking: An Assessment of Reporting in Relation to the Standards for Reporting of Diagnostic Accuracy Studies Statement.

OBJECTIVE: The objective of this study was to assess the quality of reporting of full-text articles of dental diagnostic accuracy studies published in eight leading speciality dental journals in relation to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement. METHODS: The full articles of all included studies were assessed for their adherence to the 30-item STARD checklist by two researchers independently. A score of 0-2 was attributed to each item. Inter-rater agreement was assessed. Univariate and multivariate linear regression analyses were carried out to evaluate differences in reporting qualities between journals and whether certain variables influenced reporting qualities. RESULTS: A total of 145 articles were identified. Full-article STARD checklist items relating to methodology and results were poorly reported. The overall mean quality score for full articles was 28.75. Articles published in the Journal of Cranio-Maxillofacial Surgery obtained the highest quality score. In the multivariate analysis, articles published in the Journal of Cranio-Maxillofacial Surgery had significantly higher reporting quality scores than those published in the European Journal of Orthodontics (ß = -6.97, 95% confidence interval [CI]: -11.62, -2.30, P < .05), the Journal of Prosthetic Dentistry (ß = -8.01, 95% CI: -14.60, -1.41, P < .05) and Oral Diseases (ß = -6.72, 95% CI: -11.57, -1.86, P < .05). Reporting quality improved each year (P < .028). CONCLUSION: Adherence of full articles to the STARD is suboptimal in dental journals.

Marauding terrorist attack (MTA): prehospital considerations.

Terrorist attacks are increasing each year as are the number of deaths associated with them. Recent incidents have seen a shift in tactics with the use of multiple terrorists across multiple locations with firearms or knives, referred to as the marauding terrorist attack. These methods are becoming more prevalent alongside the use of vehicles deliberately aimed at pedestrians. Management of these incidents can be challenging. Not only it involves a large number of casualties but also the management of a dynamic scene in terms of both location and threat from attack. In order to improve response, and potentially outcomes, a system or response needs to have preplanned and practised procedures in place. This article reviews major incident management for those unfamiliar with current prehospital practice and details some of the findings from recent marauding terrorist firearm attacks, in particular the evolution of newer scene management tools such as 3 Echo and THREAT. It highlights the importance of haemorrhage control and the public initiatives focusing on actions during a terrorist incident.

Cavity lining in primary teeth.

DATA SOURCES: Embase, Medline, Cochrane Central, Biomed Central and Open Grey databases and bibliographies of identified studies. STUDY SELECTION: Randomised controlled trials investigating humans with primary caries lesions receiving operative treatment involving caries removal and restoration, with minimum two treatment groups comparing different cavity treatments before restoration (no lining versus lining) were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two reviewers and study quality assessed using the Cochrane risk of bias tool. Random effect meta-analysis was carried out. RESULTS: Three studies involving a total of 89 patients were included. All the studies involved primary teeth and were conducted in Brazil. Follow-up periods ranged from 26-53 months. All the studies were considered to be at high risk of bias. Restoring the cavity without lining did not significantly affect the risk of failure. The quality of the evidence was low. CONCLUSIONS: Current evidence does not support strong recommendations to use or not to use liners after caries removal and before restoring cavities. Our findings are restricted to primary teeth after selective excavation, with only one liner (calcium hydroxide) being used for comparison.

Good short-term survival rates for posterior resin composite restorations.

DATA SOURCES: PubMed, the Cochrane Library and the databases of the Centre for Reviews and Dissemination were searched. STUDY SELECTION: Prospective randomised controlled trials (RCTs), clinical controlled trials (CCTs) and observational studies of Class I and/or Class II resin composite restorations with a sample size of more than 40 individuals or teeth and longer than four years follow-up were considered. RESULTS: Eight studies involving a total of 910 restorations in 420 patients were included. Seven of the eight studies were completed by the same research group with follow-up times ranging from four to 12 years. There were 80 failures of restorations in total, ranging from two to 17 per study. A majority of the fractures of the restoration or the tooth and endodontic complications occurred during the first three years of follow-up. Caries occurred later, more than 75% after three years in service. The overall incidence rate for all causes of failure was 1.55 lost restorations per 100 restoration years. Survival rate at four years = 0.93 (95% CI; 0.91- 0.95). One study (74 teeth) provided data at 12 years with a survival rate = 0.86 (95% CI; 0.82;0.89). The most common biological reason for failure (a total of 31 restorations) was secondary caries, with or without fracture of the restoration. The overall quality of the evidence was low. CONCLUSIONS: The overall survival proportion of posterior resin composite restorations is high. The major reasons for failure are secondary caries and restoration fracture, which supports the importance of adequate follow-up time as secondary caries often occurred after three years or later.

Ubiquitin specific peptidase (USP37) mediated effects in microscaffold-encapsulated cells: a comprehensive study on growth, proliferation and EMT.

Though significant advances have been made in developing therapeutic strategies for cancer, suitable in vitro models for mechanistically identifying relevant drug targets and understanding disease progression are still lacking. Most studies are generally performed using two-dimensional (2D) models, since these models can be readily established and allow high throughput assays. However, these models have also been reported as the reason for unreliable pre-clinical information. To avoid this discrepancy, three-dimensional (3D) cell culture models have been established and have demonstrated the potential to provide alternative ways to study tissue behavior. However, most of these models first require optimization and cell cultures with a certain density, thus adding a prepping step in the platform before it can be used for any studies. This limits their use in studies where the fundamental understanding of biological processes must be carried out in a short time frame. In this study, we developed a 3D cell culture system that tests a less explored cancer therapeutic target-the deubiquitinating enzyme ubiquitin specific peptidase 37 (USP37)-in different cancer cell lines using sensitive carbon dot pH nanosensors, which provides a rapid model for studies compared to the parallel model available commercially. This enzyme is found to be elevated in different cancers and has been reported to play a role in cell cycle regulation, oncogenesis and metastasis. However, the confirmation of the role of USP37 downregulation in cellular proliferation via appropriate in vitro 3D models has not been demonstrated. To establish the applicability of the developed 3D platform in studying such oncogenes, classical 2D models have been used in this study for identifying the role of USP37 in tumor progression and metastasis. The data clearly suggests that this ingeniously developed 3D cell culture system is a better alternative to 2D models to study the growth and migration of different cancer cell lines on depletion of oncogenic proteins like USP37 and its effect on epithelial-mesenchymal transition (EMT) markers, and it can further be targeted as a viable therapeutic option.

The future of cancer treatment: combining radiotherapy with immunotherapy.

Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other's beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell's genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.

Bergenin inhibits growth of human cervical cancer cells by decreasing Galectin-3 and MMP-9 expression.

Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.

Argon Beam Coagulation as an Adjuvant for Extended Curettage for Giant Cell Tumors of the Bone: A Study of 50 Cases.

Objective Extended curettage with adjuvants of giant cell tumors of bone is associated with a lower rate of recurrence of the tumor while preserving the adjacent joint. The present study was conducted to estimate the recurrence rate and functional outcome after using argon beam as an adjuvant for extended curettage. Methods We selected 50 patients with giant cell tumors, meeting all the inclusion criteria, who underwent extended curettage using high speed burr and argon beam photocoagulation between July 2016 to January 2019. On their follow-up visit, they were assessed for any complaints of pain and signs like tenderness, locally raised temperature, and decreased range of motion of the adjacent joint. Radiologically, the patients were assessed for any increased lucency around the cement mantle and uptake of the subarticular graft. Musculoskeletal Tumor Society Score (MSTS) was administered to the patients, and range of motion of the adjacent joint was compared with the contralateral joint. Results Recurrence was found in 4 patients, that is, an 8% recurrence rate. Twenty-six out of 28 patients with a tumor in the lower limb had a grade-5 weight bearing status 6 months from the surgery, and their range of motion was comparable to contralateral healthy joint with an average MSTS score of 27 (18-30). Conclusion Extended curettage of giant cell tumors using argon beam coagulation is associated with low recurrence rates of the tumor and is an effective modality in the treatment of these tumors besides having a functional outcome comparable to the healthy limb.

Cyclin-dependent kinases in cancer: Role, regulation, and therapeutic targeting.

Regulated cell division is one of the fundamental phenomena which is the basis of all life on earth. Even a single base pair mutation in DNA leads to the production of the dysregulated protein that can have catastrophic consequences. Cell division is tightly controlled and orchestrated by proteins called cyclins and cyclin-dependent kinase (CDKs), which serve as licensing factors during different phases of cell division. Dysregulated cell division is one of the most important hallmarks of cancer and is commonly associated with a mutation in cyclins and CDKs along with tumor suppressor proteins. Therefore, targeting the component of the cell cycle which leads to these characteristics would be an effective strategy for treating cancers. Specifically, Cyclin-dependent kinases (CDKs) involved in cell cycle regulation have been identified to be overexpressed in many cancers. Many studies indicate that oncogenesis occurs in cancerous cells by the overactivity of different CDKs, which impact cell cycle progression and checkpoint dysregulation which is responsible for development of tumor. The development of CDK inhibitors has emerged as a promising and novel approach for cancer treatment in both solid and hematological malignancies. Some of the novel CDK inhibitors have shown remarkable results in clinical trials, such as-Ribociclib®, Palbociclib® and Abemaciclib®, which are CDK4/6 inhibitors and have received FDA approval for the treatment of breast cancer. In this chapter, we discuss the molecular mechanism through which cyclins and CDKs regulate cell cycle progression and the emergence of cyclins and CDKs as rational targets in cancer. We also discuss recent advances in developing CDK inhibitors, which have emerged as a novel class of inhibitors, and their associated toxicities in recent years.