LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.

Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.

Analysis of the effect of staple line reinforcement on leaking and bleeding after sleeve gastrectomy from the UK National Bariatric Surgery Registry.

INTRODUCTION: Sleeve gastrectomy (SG) is currently the most frequently performed procedure for obesity worldwide. Staple line reinforcement (SLR) has been suggested as a strategy to reduce the risk of staple line leak or bleeding; however, its use for SG in the United Kingdom (UK) is unknown. This study examined the effect of SLR on the development of postoperative complications from SG using a large national dataset from the UK. METHODS: Patients undergoing either primary or revision SG over 10 years from Jan 2012 to Dec 2021 were identified by the National Bariatric Surgery Registry. Comparative and logistic regression analyses were undertaken to determine the effect of SLR on staple line leak and bleeding. RESULTS: During this time, 14,231 patients underwent SG for whom there were complete data. Of these, 76.5% were female and the median age was 46 years (IQR: 36-53). The rate of surgical complications was 2.3% (n = 219/14,231). The incidence of bleeding was 1.3% (n = 179/14,231) and leak was 1.0% (n = 140/14,231). Over time, the use of SLR of any variety declined significantly from 99.7% in 2012 to 57.3% in 2021 (p < 0.001). Multivariable (adjusted) regression analysis demonstrated that neither the use of nor the type of reinforcement had any effect on the rate of bleeding or leaking. CONCLUSION: SLR for SG has declined in the UK since 2012. There were no differences in staple line leak or bleed with or without reinforcement.

Magnetic sphincter augmentation in the management of gastro-esophageal reflux disease: A systematic review and meta-analysis.

BACKGROUND: Magnetic sphincter augmentation (MSA) through placement of the LINX device is an alternative to fundoplication in the management of gastro-esophageal reflux disease (GERD). This systematic review and meta-analysis aimed to assess efficacy, quality of life and safety in patients that underwent MSA, with a comparison to fundoplication. METHODS: A literature search of MEDLINE, Embase, Emcare, Scopus, Web of Science and Cochrane library databases was performed for studies that reported data on outcomes of MSA, with or without a comparison group undergoing fundoplication, for GERD from January 2000 to January 2023. Meta-analysis was performed using random-effect models and between-study heterogeneity was assessed. RESULTS: Thirty-nine studies with 8,075 patients were included: 6,983 patients underwent MSA and 1,092 patients had laparoscopic fundoplication procedure. Ten of these studies (seven retrospective and three prospective) directly compared MSA with fundoplication. A higher proportion of individuals successfully discontinued proton-pump inhibitors (P<0.001; WMD 0.83; 95% CI 0.72-0.93; I2=96.8%) and had higher patient satisfaction (P<0.001; WMD 0.85; 95% CI 0.78-0.93; I2=85.2%) following MSA when compared to fundoplication. Functional outcomes were better after MSA than after fundoplication including ability to belch (P<0.001; WMD 0.96; 95% CI 0.93-0.98; I2=67.8) and emesis (P<0.001; WMD 0.92; 95% CI 0.89-0.95; I2=42.8%), and bloating (P=0.003; WMD 0.20; 95% CI 0.07-0.33; I2=97.0%). MSA had higher rates of dysphagia (P=0.001; WMD 0.41; 95% CI 0.17-0.65; I2=97.3%) when compared to fundoplication. The overall erosion and removal rate following MSA was 0.24% and 3.9% respectively, with no difference in surgical re-intervention rates between MSA and fundoplication (P=0.446; WMD 0.001; 95% CI -0.001-0.002; I2 =78.5%). CONCLUSIONS: MSA is a safe and effective procedure at reducing symptom burden of GERD and can potentially improve patient satisfaction and functional outcomes. However, randomized controlled trials directly comparing MSA with fundoplication are necessary to determine where MSA precisely fits in the management pathway of GERD.

Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Retinal complications post posterior chamber phakic intraocular lens implantation at a tertiary eye hospital in the Eastern Province of Saudi Arabia.

PURPOSE: Phakic intraocular lenses treat higher degrees of myopia not possible previously with conventional refractive surgery. The aim of this study is to report the incidence and risk factors of retinal complications after posterior chamber PIOL implantation and assess the differences in biometric parameters between patients who developed such complications versus those who did not. METHODS: This retrospective study recruited 514 patients who underwent ICL implantation to correct myopia at a tertiary eye hospital center in the Eastern province of Saudi Arabia. Follow up period was at least one year. Medical records of the patients were reviewed to obtain the required data. Associations between respondents' characteristics and retinal complications were evaluated using the Chi-squared test. RESULTS: The mean (SD) age was 27.7 (± 6.5) years ranging from 18 to 47. Laser treatment was performed in 14 cases (2.7%). Retinal complications occurred in six cases (1.2%). The risk of retinal complication was significantly higher among patients with high axial length (OR = 1.3, 95% CI 1.2, 1.4) and patients with high pre-spherical equivalent before ICL (OR = 1.09, 95% CI 1.03, 1.4). CONCLUSION: Patients with higher axial length and higher pre-spherical equivalent before ICL implantation are at high risk of retinal complications.

Recent trends and advances in novel formulations as an armament in Bcl-2/Bax targeted breast cancer.

Breast cancer (BC) remains a significant health burden worldwide, necessitating the development of innovative therapeutic strategies. The B-cell lymphoma 2 (Bcl-2) family proteins, Bcl-2 and Bax, play a crucial role in regulating apoptosis and thus are promising targets for BC therapy. We focus on the recent advancements in novel formulations that specifically target Bcl-2/Bax pathway to combat BC. It provides an overview on biological functions of Bcl-2/Bax in apoptosis regulation, emphasizing their significance in pathogenesis and progression of the disease while covering the numerous therapeutic approaches aimed at modulating the Bcl-2/Bax pathway, including small-molecule inhibitors, peptides, gene-based therapies and other repurposed drugs harboured onto cutting-edge technologies and nanocarrier systems employed to enhance the targeted delivery of Bcl-2/Bax inhibitors tumor cells. These advanced formulations aim to improve therapeutic efficacy, minimize off-target effects, and overcome drug resistance, offering promising prospects in its treatment. In conclusion, it illuminates the diverse and evolving landscape of novel formulations as an essential armament in targeting these proteins while bridging and unravelling the obscurity of Bcl-2/Bax pathway-targeted drug delivery systems which are presently in their nascent stages of exploration for BC therapy which can benefit researchers, clinicians, and pharmaceutical scientists.

Implementation of a novel thoracostomy tube trainer with real-time feedback.

Objectives: Simulation-based training leads to improved clinical performance but may be influenced by quality and frequency of training. Within simulation training, chest tube insertion remains a challenge as one of the main pitfalls of insertion is a controlled pleural entry. This study evaluates the efficacy of a novel training model with real-time pressure monitoring, the average force to pleural entry in a model and the utility of audio and visual feedback. Methods: This proprietary training model comprised a modified Kelly clamp device with three force sensors at the index finger (sensor 1) and two finger loops (sensors 2 and 3), and a manikin with a replaceable chest wall pad. Standard force values (Newtons (N)) were obtained by experts; expert data revealed that 3-5 s was an acceptable time range to complete the chest tube insertion. Participant level ranged from Post-graduate Year (PGY)-1 to PGY-6 with 13 total participants. Each individual was provided an introduction to the procedure and chest tube trainer. Force (N) and time (ms) measurements were obtained from entry through dermis to pleural space puncture. A significant pressure drop suggested puncturing through the chest wall (completion of the procedure). Results: Force data were captured during each phase of the procedure-linear, plateau, and drop. Linear phase (~3000 ms) was from start of procedure to point of maximum force (<30 N). Plateau phase was from maximum force to just before a drop in pressure. Drop phase was a drop in pressure by 5+ N in a span of 150 ms signaling completion of procedure. All participants were able to complete the task successfully. Force for pleural entry ranged from 17 N to 30 N; time to pleural entry ranged from 7500 to 15 000 ms. There was variability in use of all three sensors. All participants used the index sensor, however there was variability in the use of the loop sensors depending on the handedness of the participant. Left-handed users relied more on sensors 1 and 3 while right-handed users relied more on sensors 1 and 2. Given this variability, only force measurements from sensor 1 were used for assessment. Conclusions: This novel force-sensing chest tube trainer with continuous pressuring monitoring has a wide range of applications in simulation-based training of emergency surgical tasks. Next steps include evaluating its impact on accuracy and efficiency. Applications of real-time feedback measuring force are broad, including vascular access, trocar placement and other common procedures. Level of evidence: Level IV, prospective study.

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the digestive tract with increasing prevalence globally. Although venous thromboembolism (VTE) is a major complication in IBD patients, it is often underappreciated with limited tools for risk stratification. AIM: To estimate the proportion of VTE among IBD patients and assess genetic risk factors (monogenic and polygenic) for VTE. METHODS: Incident VTE was followed for 8465 IBD patients in the UK Biobank (UKB). The associations of VTE with F5 factor V leiden (FVL) mutation, F2 G20210A prothrombin gene mutation (PGM), and polygenic score (PGS003332) were tested using Cox hazards regression analysis, adjusting for age at IBD diagnosis, gender, and genetic background (top 10 principal components). The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve (AUC). RESULTS: The overall proportion of incident VTE was 4.70% in IBD patients and was similar for CD (4.46%), UC (4.49%), and unclassified (6.42%), and comparable to that of cancer patients (4.66%) who are well-known at increased risk for VTE. Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers, hazard ratio (HR) was 1.94, 95% confidence interval (CI): 1.42-2.65. In contrast, patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores (middle 8 deciles), HR was 2.06 (95%CI: 1.57-2.71). The AUC for differentiating VTE diagnosis was 0.64 (95%CI: 0.61-0.67), 0.68 (95%CI: 0.66-0.71), and 0.69 (95%CI: 0.66-0.71), respectively, for F5/F2 mutation carriers, PGS, and combined. CONCLUSION: Similar to cancer patients, VTE complications are common in IBD patients. PGS provides more informative risk information than F5/F2 mutations (FVL and PGM) for personalized thromboprophylaxis.

A Rare Case of Therapy-Related B-cell Acute Lymphoblastic Leukemia Arising From Acute Myeloid Leukemia.

Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare potential complication of chemotherapy. We describe the case of a 47-year-old male patient who was originally diagnosed with t(8;21) positive acute myeloid leukemia (AML) in 2019, received chemotherapy, achieved remission, and was disease-free for the next two years. During a routine follow-up in 2022, he was found to have developed subclinical pancytopenia, and further studies indicated a diagnosis of pH-negative, near-tetraploid B-cell acute lymphoblastic leukemia (B-ALL) that was positive for a Tier 1 TP53 mutation, consistent with t-ALL. The patient had a prolonged treatment course complicated by social factors, such as the impact of both disease and treatment on his ability to work enough to make a living and live life with the quality he desired. The patient elected to pause treatment and resume it at a later date, after which, unfortunately, significant disease progression occurred and the patient died from complicating neutropenic sepsis and variceal bleeding. This case illustrates the challenges of managing social circumstances and patient goals in the setting of medically necessary but potentially harsh treatment courses. Given the aggressive nature of t-ALL and its overall poor prognosis, goals of care must be re-evaluated and discussed often to ensure alignment of therapy with a patient's wishes.

Control of TGFß signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.

Transforming growth factor ß (TGFß) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFß signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFß signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFß signalling in multiple models. Interestingly, TRIP12 control of TGFß signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFß signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFß signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFß mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFß induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFß signalling in health and disease.

Epigenetic inhibitors and their role in cancer therapy.

Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.

In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40.

Identifying molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex.

Bariatric surgery provision in response to the COVID-19 pandemic: retrospective cohort study of a national registry.

BACKGROUND: When surgery resumed following the outbreak of the COVID-19 pandemic, guidelines recommended the prioritization of patients with greater obesity-related co-morbidities and/or higher body mass index. OBJECTIVE: The aim of this study was to record the effect of the pandemic on total number, patient demographics, and perioperative outcomes of elective bariatric surgery patients in the United Kingdom. SETTING AND METHODS: The United Kingdom National Bariatric Surgical Registry was used to identify patients who underwent elective bariatric surgery during the pandemic (1 yr from April 1, 2020). Characteristics of this group were compared with those of a pre-pandemic cohort. Primary outcomes were case volume, case mix, and providers. National Health Service cases were analyzed for baseline health status and perioperative outcomes. Fisher exact, χ2, and Student t tests were used as appropriate. RESULTS: The total number of cases decreased to one third of pre-pandemic volume (8615 to 2930). The decrease in operating volume varied, with 36 hospitals (45%) experiencing a 75%-100% reduction. Cases performed in the National Health Service fell from 74% to 53% (P < .0001). There was no change in baseline body mass index (45.2 ± 8.3 kg/m2 from 45.5 ± 8.3 kg/m2; P = .23) or prevalence of type 2 diabetes (26% from 26%; P = .99). Length of stay (median 2 d) and surgical complication rate (1.4% from 2.0%; relative risk = .71; 95% CI .45-1.12; P = .13) were unchanged. CONCLUSIONS: In the context of a dramatic reduction in elective bariatric surgery due to the COVID-19 pandemic, patients with more severe co-morbidities were not prioritized for surgery. These findings should inform preparation for future crises.

Adjunct fixation in upper extremity long bone fracture plating.

PURPOSE: A variety of adjunct fixation methods to supplement primary plate and screw constructs are available. There are no large clinical series of these techniques in the upper extremity. The purpose of this study was to review patients with upper extremity fractures that underwent primary plating with adjunct fixation. METHODS: This study was a retrospective review of plate fixation of humeral, radial and ulnar fractures over a 12-year period. Measurable outcomes for this study included rates of non-union, complications, and implant removal. RESULTS: Thirty-nine humeral shaft fractures had supplemental fixation 97% of the time, with a 100% union rate. Supplemental fixation was used in 79% of forearm cases. There was a 98% initial union rate in 48 acutely plated forearm fractures. CONCLUSION: Although a variety of techniques were employed, the mini-fragment (2.7 mm or smaller) was the most common strategy for adjunctive fixation of long bone fractures in the upper extremity.

Medicolegal Cases in Bariatric Surgery in the United Kingdom.

PURPOSE OF REVIEW: To evaluate the current state of bariatric medicolegal activity and explore the reasons of litigation in bariatric surgery. The underlying legal principles in bariatric medicolegal cases and most frequent pitfalls will also be discussed. RECENT FINDINGS: There is a growing number of litigations in bariatric surgery, particularly relating to complications and long waiting lists for bariatric surgery within the public-funded health systems. The main issues are related to consent, lack of follow-up, delayed identification of complications and lack of appropriate emergency management of complications, involving bariatric surgeons, clinicians, general practitioners and multidisciplinary team members. Appropriate multidisciplinary involvement pre- and postoperatively and robust follow-up protocols can help to mitigate the risks. Bariatric surgery requires a unique paradigm with a multidisciplinary approach both pre- and postoperatively to improve the long-term functional outcomes of patients. There is a rising incidence of medicolegal claims following bariatric surgery. The underlying reasons for this are multifactorial including an increase in the volume of surgery, high patient expectations, the incidence of long-term postoperative complications and the requirement of long-term follow-up.

In Vitro Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.

Identifying novel molecular mechanisms of exhausted CD8 T cells (T ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T ex can be costly and inefficient. In vitro models of T ex are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T ex . We leveraged this model of in vitro chronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of T ex . By developing and benchmarking an in vitro model of T ex , we demonstrate the utility of mechanistically annotated in vitro models of T ex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel T ex biology.

Effect of an antimicrobial stewardship program in the prevention of antibiotic misuse in patients with spinal cord injury undergoing minor urologic procedures: a single-group, quasi-experiment study.

BACKGROUND: Antimicrobial stewardship programs (ASPs) are an internationally recognized strategy for reducing antimicrobial resistance while maintaining patient safety. ASP activities include the restriction of broad-spectrum antibiotics, the establishment of hospital guidelines based on antibiograms, and the promotion of appropriate antibiotic use. This study aimed to determine whether the implementation of antimicrobial stewardship practices improved the effects of a peri-procedure antibiotic prophylaxis prescribed by urologists for patients with spinal cord injury/disease (SCI/D) undergoing minor urological procedures at a tertiary care hospital. METHODS: This single-group, quasi-experiment study included adult patients with SCI/D who required minor urological procedures (cystoscopy, cytobotox, cystolitholapaxy, and urodynamic study) and who were hospitalized between 2012 and 2020. RESULTS: In total, 233 patients were included in each of the pre- and post-ASP implantation groups. There was a significant reduction in antibiotic use among patients who received a pre-procedure antimicrobial prophylaxis in the post- compared to the pre-implementation group (45.9% vs. 24.46%, p < 0.0001), and there was a highly significant reduction in the post- compared to the pre-implementation group in the number who received a post-procedure prophylaxis (16.7% vs. 1.2%, p < 0.0001). CONCLUSION: ASP implementation is a highly effective strategy for reducing the use of peri-procedure antimicrobial prophylaxes in patients with SCI/D injuries undergoing minor urological procedures.

FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2.

FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.