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ABSTRACTThe rising rate of antimicrobial resistance continues to threaten global public health. Further hastening antimicrobial resistance is the lack of new antibiotics against new targets. The bacterial enzyme, 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), is thought to play important roles in central metabolism, including processes required for pathogen adaptation to fluctuating host environments. Thus, impairing DXPS function represents a possible new antibacterial strategy. We previously investigated a DXPS-dependent metabolic adaptation as a potential target in uropathogenic Escherichia coli (UPEC) associated with urinary tract infection (UTI), using the DXPS-selective inhibitor butyl acetylphosphonate (BAP). However, investigations of DXPS inhibitors in vivo have not been conducted. The goal of the present study is to advance DXPS inhibitors as in vivo probes and assess the potential of inhibiting DXPS as a strategy to prevent UTI in vivo. We show that BAP was well-tolerated at high doses in mice and displayed a favorable pharmacokinetic profile for studies in a mouse model of UTI. Further, an alkyl acetylphosphonate prodrug (homopropargyl acetylphosphonate, pro-hpAP) was significantly more potent against UPEC in urine culture and exhibited good exposure in the urinary tract after systemic dosing. Prophylactic treatment with either BAP or pro-hpAP led to a partial protective effect against UTI, with the prodrug displaying improved efficacy compared to BAP. Overall, our results highlight the potential for DXPS inhibitors as in vivo probes and establish preliminary evidence that inhibiting DXPS impairs UPEC colonization in a mouse model of UTI.IMPORTANCENew antibiotics against new targets are needed to prevent an antimicrobial resistance crisis. Unfortunately, antibiotic discovery has slowed, and many newly FDA-approved antibiotics do not inhibit new targets. Alkyl acetylphosphonates (alkyl APs), which inhibit the enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), represent a new possible class of compounds as there are no FDA-approved DXPS inhibitors. To our knowledge, this is the first study demonstrating the in vivo safety, pharmacokinetics, and efficacy of alkyl APs in a urinary tract infection mouse model.

Abstract Background Despite over two years of COVID-19 worldwide, the outbreak of the Omicron variant has given rise to an unprecedented surge of infection with diverse lockdown measures implemented globally. Whether the emergence of a new wave of COVID-19 could further affect mental health in the population after nearly two years of the pandemic remains to be addressed. Furthermore, whether changes in smartphone overuse behaviours and physical activity – both of which are particularly relevant to young people – would together contribute to changes in distress symptoms during this wave of COVID-19 was also examined. Methods A total of 248 young people from an ongoing household-based epidemiological study in Hong Kong who completed their baseline assessments prior to the Omicron variant outbreak, i.e., fifth wave of COVID-19 (July–November 2021), were invited for a 6-month follow-up study during this wave of infection (January–April 2022) (mean age = 19.7 years, SD = 2.7; 58.9% females). At both time points, levels of global distress symptoms, perceived stress, smartphone overuse, frequency of engagement in vigorous physical activity, and other potential risk and protective factors were assessed. Results The proportion of young people presenting moderate-to-severe distress (6-item Kessler Psychological Distress Scale ≥ 5) significantly increased from 45.6 to 54.4% during the fifth wave of COVID-19 (p

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention.

Summary: Background: Hong Kong is among the many populations that has experienced the combined impacts of social unrest and the COVID-19 pandemic. Despite concerns about further deteriorations in youth mental health globally, few epidemiological studies have been conducted to examine the prevalence and correlates of major depressive episode (MDE) and other major psychiatric disorders across periods of population-level changes using diagnostic interviews. Methods: We conducted a territory-wide household-based epidemiological study from 2019 to 2022 targeting young people aged 15–24 years. MDE, generalised anxiety disorder (GAD), panic disorder (PD), and bipolar disorder (BD) were assessed using the Composite International Diagnostic Interview–Screening Scales in 3340 young people. Psychotic disorders were assessed by experienced psychiatrists according to the DSM. Help-seeking patterns were also explored. Findings: 16.6% had any mental disorder (13.7% 12-month MDE, 2.3% BD, 2.1% GAD, 1.0% PD, 0.6% psychotic disorder). The prevalence of MDE increased from 13.2% during period 1 (May 2019–June 2020) to 18.1% during period 2 (July–December 2020), followed by 14.0% during period 3 (January–June 2021) and 13.2% during period 4 (July 2021–June 2022). Different stressors uniquely contributed to MDE across periods: social unrest-related stressors during period 1, COVID-19 stressors during period 2, and personal stressors during periods 3–4. Lower resilience, loneliness, frequent nightmares, and childhood adversity were consistently associated with MDE. Compared to other conditions, those with MDE showed the lowest service utilisation rate (16.7%). Perceiving services to “cost too much” and “talked to friends or relatives instead” were among the major reasons for not seeking help. MDE was also significantly associated with poorer functioning and health-related quality of life. Interpretation: MDE can be sensitive to population-level changes, although its persistently elevated prevalence across the study period is of concern. Efforts to mitigate their impacts on youth mental health alongside personal risk factors are needed. Further work is required to increase the availability and acceptability of youth-targeted mental health services. Funding: Food and Health Bureau (HKSAR Government).

Renal oncocytomas are commonly reported in association with Birt-Hogg-Dube (BHS) syndrome, while BHD-associated oncocytomas of the parotid gland are rare. To date, there have been only 11 cases of BHD-associated parotid gland oncocytoma, without a reported case of malignant transformation. We present the first reported case of oncocytic carcinoma of the parotid gland associated with BHD, with radiologic and histologic correlation. This case establishes that BHD-associated parotid oncocytic lesions, previously identified only as benign oncocytomas in the literature to date, can undergo malignant transformation, and should potentially be regarded with a higher index of suspicion and lower threshold for aggressive management.

ObjectivesTo identify combined clinical, radiomic, and delta-radiomic features in metastatic gastroesophageal adenocarcinomas (GEAs) that may predict survival outcomes.MethodsA total of 166 patients with metastatic GEAs on palliative chemotherapy with baseline and treatment/follow-up (8–12 weeks) contrast-enhanced CT were retrospectively identified. Demographic and clinical data were collected. Three-dimensional whole-lesional radiomic analysis was performed on the treatment/follow-up scans. “Delta” radiomic features were calculated based on the change in radiomic parameters compared to the baseline. The univariable analysis (UVA) Cox proportional hazards model was used to select clinical variables predictive of overall survival (OS) and progression-free survival (PFS) (p-value

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood. Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC. Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial. Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints. Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline ( p = 0.0030) and progression ( p = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints ( p

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Abstract Background Testicular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Methods Adult cisplatin‐treated testicular cancer survivors were enrolled. High‐Performance Liquid Chromatography‐tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed. Results From 11/2017 to 12/2019, 38 patients (median age 32 years; range: 19–52) were enrolled. Median cumulative cisplatin dose was 301 mg/m2 (range: 274–404). Platinum levels were higher in semen than in blood (p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing (r = −0.34; p = 0.09) nor cumulative dose (r = −0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p

Abstract Background Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD). Methods Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on “3 + 3” design within each HD group. PK samples were collected at cycle 1 days 15-16. Results Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26). Conclusions RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients – 1.5 mg QD in Mod group, and 1 mg QD in Sev group. Trial registration This study was registered in the ClinicalTrials.gov website ( NCT 02070549 ) on February 25, 2014. .

Abstract Objective Clinicians rely on patient self‐report of impairment during seizures for decisions including driving eligibility. However, the reliability of patient reports on cognitive and behavioral functions during seizures remains unknown. Methods We administered a daily questionnaire to epilepsy patients undergoing continuous video‐EEG monitoring, asking about responsiveness, speech, memory, awareness, and consciousness during seizures in the preceding 24 hours. We also administered a questionnaire upon admission about responsiveness, speech, and awareness during seizures. Subjective questionnaire answers were compared with objective behavioral ratings on video review. Criteria for agreement were Cohen’s kappa >0.60 and proportions of positive and negative agreement both >0.75. Results We analyzed 86 epileptic seizures in 39 patients. Memory report on the daily questionnaire met criteria for agreement with video review (κ = 0.674 for early, 0.743 for late recall). Subjective report of awareness also met agreement criteria with video ratings of memory (κ = 0.673 early, 0.774 late). Concordance for speech was relatively good (κ = 0.679) but did not meet agreement criteria, nor did responsiveness or consciousness. On the admission questionnaire, agreement criteria were met for subjective report of awareness versus video ratings of memory (κ = 0.814 early, 0.806 late), but not for other comparisons. Interpretation Patient self‐report of memory or awareness showed the best concordance with objective memory impairment during seizures. Self‐report of impairment in other categories was less reliable. These findings suggest that patient reports about impaired memory during seizures may be most reliable, and otherwise determining functional impairments should be based on objective observations.

Pathogenic bacteria possess a remarkable ability to adapt to fluctuating host environments and cause infection. Disturbing bacterial central metabolism through inhibition of 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) has the potential to hinder bacterial adaptation, representing a new antibacterial strategy. DXPS functions at a critical metabolic branchpoint to produce the metabolite DXP, a precursor to pyridoxal-5-phosphate (PLP), thiamin diphosphate (ThDP) and isoprenoids presumed essential for metabolic adaptation in nutrient-limited host environments. However, specific roles of DXPS in bacterial adaptations that rely on vitamins or isoprenoids have not been studied. Here we investigate DXPS function in an adaptation of uropathogenic E. coli (UPEC) to d-serine (d-Ser), a bacteriostatic host metabolite that is present at high concentrations in the urinary tract. UPEC adapt to d-Ser by producing a PLP-dependent deaminase, DsdA, that converts d-Ser to pyruvate, pointing to a role for DXPS-dependent PLP synthesis in this adaptation. Using a DXPS-selective probe, butyl acetylphosphonate (BAP), and leveraging the toxic effects of d-Ser, we reveal a link between DXPS activity and d-Ser catabolism. We find that UPEC are sensitized to d-Ser and produce sustained higher levels of DsdA to catabolize d-Ser in the presence of BAP. In addition, BAP activity in the presence of d-Ser is suppressed by β-alanine, the product of aspartate decarboxylase PanD targeted by d-Ser. This BAP-dependent sensitivity to d-Ser marks a metabolic vulnerability that can be exploited to design combination therapies. As a starting point, we show that combining inhibitors of DXPS and CoA biosynthesis displays synergy against UPEC grown in urine where there is increased dependence on the TCA cycle and gluconeogenesis from amino acids. Thus, this study provides the first evidence for a DXPS-dependent metabolic adaptation in a bacterial pathogen and demonstrates how this might be leveraged for development of antibacterial strategies against clinically relevant pathogens.

Abstract Background The goal of surveillance testing is to enable curative salvage therapy through early disease detection, however supporting evidence in gastroesophageal adenocarcinoma is limited. We evaluated frequency of successful salvage therapy and outcomes in patients who underwent surveillance. Methods A single‐site, retrospective cohort study was conducted to identify all patients who received curative resection for gastroesophageal adenocarcinoma. Surveillance testing were those investigations not triggered by abnormal symptoms, physical examination, or blood tests. Successful salvage therapy was any potentially curative therapy for disease recurrence which resulted in postrecurrence disease‐free survival ≥2 years. Time‐to‐event data were analyzed using the Kaplan‐Meier method and log rank tests. Results Between 2011 and 2016, 210 consecutive patients were reviewed. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%) or multimodality therapy (71%). Adjuvant therapy was administered in 35%. At median follow‐up of 38.3 months, 5‐year overall survival (OS) rate was 56%. Among 97 recurrences, 53% were surveillance‐detected, and 46% were symptomatic. None was detected by surveillance endoscopy. Median time‐to‐recurrence (TTR) was 14.8 months. Recurrences included locoregional only (4%), distant (86%), and both (10%). Salvage therapy was attempted in 15 patients, 4 were successful. Compared to symptomatic recurrences, patients with surveillance‐detected recurrences had longer median OS (36.2 vs 23.7 months, P = .004) and postrecurrence survival (PRS, 16.5 vs 4.6 months, P

Background: Mouse models are highly effective for studying the pathophysiology of lung adenocarcinoma and evaluating new treatment strategies. Treatment efficacy is primarily determined by the total tumor burden measured on excised tumor specimens. The measurement process is time-consuming and prone to human errors. To address this issue, we developed a novel deep learning model to segment lung tumor foci on digitally scanned hematoxylin and eosin (H&E) histology slides. Methods: Digital slides of 239 mice from 9 experimental cohorts were split into training (n=137), validation (n=37), and testing cohorts (n=65). Image patches of 500×500 pixels were extracted from 5× and 10× magnifications, along with binary masks of expert annotations representing ground-truth tumor regions. Deep learning models utilizing DeepLabV3+ and UNet architectures were trained for binary segmentation of tumor foci under varying stain normalization conditions. The performance of algorithm segmentation was assessed by Dice Coefficient, and detection was evaluated by sensitivity and positive-predictive value (PPV). Results: The best model on patch-based validation was DeepLabV3+ using a Resnet-50 backbone, which achieved Dice 0.890 and 0.873 on validation and testing cohort, respectively. This result corresponded to 91.3 Sensitivity and 51.0 PPV in the validation cohort and 93.7 Sensitivity and 51.4 PPV in the testing cohort. False positives could be reduced 10-fold with thresholding artificial intelligence (AI) predicted output by area, without negative impact on Dice Coefficient. Evaluation at various stain normalization strategies did not demonstrate improvement from the baseline model. Conclusions: A robust AI-based algorithm for detecting and segmenting lung tumor foci in the pre-clinical mouse models was developed. The output of this algorithm is compatible with open-source software that researchers commonly use.

Purpose: Cerebral cavernous malformations are common central nervous system vascular malformations. They are typically a discrete, well-circumscribed cluster of thin-walled vascular sinusoids with a characteristic “mulberry” or “popcorn” appearance on magnetic resonance imaging and are often surrounded by hemosiderin deposits and gliosis. These malformations can present in a variety of ways. The purpose of this paper is to demonstrate presentations of cavernous malformations through cases with associated imaging. Materials/Methods: 14 cases of cerebral cavernous malformations were retrospectively selected from a single institution from 2009 to 2019. The cases include classically appearing lesions as well as association with developmental venous anomaly and capillary telangiectasia. Results: Variations included are large partially calcified lesions, hemorrhagic lesions, atypically shaped lesions, and lesions lacking the “popcorn” appearance or hemosiderin rim. Also presented is a case with multiple lesions and cases displaying the widespread locations of lesions. Locations include the cerebrum, cerebellar vermis, medulla, periaqueductal midbrain, spinal cord, and extradural intracranial cavernous sinus. Conclusion: These cases and literature review illustrate how cerebral cavernous malformations can present. While often asymptomatic, the lesions can cause hemorrhage, seizures, and neurological deficits. They can present in atypical ways or masquerade as non-vascular lesions making diagnosis a difficult task.

Causal interactions between specific psychiatric symptoms could contribute to the heterogenous clinical trajectories observed in early psychopathology. Current diagnostic approaches merge clinical manifestations that co-occur across subjects and could significantly hinder our understanding of clinical pathways connecting individual symptoms. Network analysis techniques have emerged as alternative approaches that could help shed light on the complex dynamics of early psychopathology. The present study attempts to address the two main limitations that have in our opinion hindered the application of network approaches in the clinical setting. Firstly, we show that a multi-layer network analysis approach, can move beyond a static view of psychopathology, by providing an intuitive characterization of the role of specific symptoms in contributing to clinical trajectories over time. Secondly, we show that a Graph-Signal-Processing approach, can exploit knowledge of longitudinal interactions between symptoms, to predict clinical trajectories at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis. Novel network approaches can allow to embrace the dynamic complexity of early psychopathology and help pave the way towards a more a personalized approach to clinical care.

Commensal microbiota has emerged as an essential biomarker and regulator of both tumorigenesis and response to cancer therapy. However, our current knowledge about microbiota in cancer has been largely limited to intestinal microbiota. As a mucosal organ harboring one of the largest surface areas in the body, the lung is exposed to a variety of microbes through inhalation and micro-aspiration, and is colonized by a diverse bacterial community in both physiological and pathological conditions. Importantly, increasing evidence has linked the lung microbiome to cancer development. Studies in lung cancer patients and mouse models have revealed tumor-associated dysregulation of the local microbiome in the lung, which in turn impacts cancer progression by shaping the tumor microenvironment and modulating the activity of tumor-infiltrating immune cells. These findings not only provide novel mechanistic insight into the biology of lung cancer but also shed light on new therapeutic targets and strategies for lung cancer prevention and treatment. The goal of this review is to discuss the key findings, remaining questions, and future directions in this new and exciting field.

Diffuse-type tenosynovial giant cell tumor (D-TGCT), otherwise known as pigmented villonodular synovitis, is a locally aggressive tumor which can show multiple recurrences but is rarely associated with metastasis. A handful of studies have elucidated the imaging features and clinical course in metastatic D-TGCT with malignant transformation on histology. However, only 5 cases of metastatic D-TGCT with benign histological features have been reported in the literature, with the clinical course and prognosis reported in only 1 case. Therefore, relatively little is known about the implications of histologically benign metastasis on the role of imaging, management, and clinical outcomes. We report a case of a 51-year-old female with recurrent D-TGCT localized to the knee that metastasized to the lymph nodes and soft tissue 3 years after above-the-knee amputation and 16 years after initial diagnosis of localized D-TGCT, despite benign histologic features on lymph node excision. This case highlights the necessity of timely MRI imaging to prevent delayed diagnosis, the role of histological findings on treatment response, and clinical outcomes associated with metastasized D-TGCT. Keywords: D-TGCT, PVNS, Metastasis, Histologically benign, Tenosynovial giant cell tumor

Objective: The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death. Methods: Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography–mass spectrometry. Results: High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells. Conclusion: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents. Keywords: Statins, Dipyridamole, Prostate cancer, Mevalonate pathway, Tumor metabolism, Drug repurposing