Smoking behaviour in post-acute myocardial infarction patients: cross-sectional study.

Introduction: Heart disease remains the leading cause of death in developed countries, and cigarette smoking contributes to a significant proportion of cardiovascular-related deaths. Abstaining from tobacco use is associated with a significant reduction in the risk of recurrent myocardial infarctions. Methodology: In this cross-sectional study, 384 participants post-acute myocardial infarction (MI) were recruited through random sampling to explore the associations between smoking status and intention to quit smoking. Data collection took place over a 6-month period at a tertiary care hospital, Islamabad, Pakistan. Results: The majority of participants were male (59.9%) and fell into the age category of 46-50 years (37.5%). Heavy daily smokers comprised the largest smoking group (41.6%), and non-ST-elevated MI was the most common subtype (40.1%). Intention to quit smoking varied among participants, with the pre-contemplation stage having the highest representation (19.3%), followed by contemplation (25.8%). Notably, a significant proportion of participants expressed no intention to quit smoking (35.4%). Conclusion: Multinomial logistic regression analysis identified current smoking as a significant predictor of intention to quit in the preparation and contemplation stages. Overall, this study underscores the importance of considering smoking behaviour when evaluating the intention to quit smoking post-MI and highlights the need for tailored interventions and support strategies to address smoking cessation in this population. These findings offer valuable insights for the development of effective strategies aimed at reducing persistent smoking following MI and improving patient outcomes.

Targeting androgen biosynthesis in prostate cancer: implications on endocrine physiology.

PURPOSE OF REVIEW: Targeting specific steroidogenic enzymes is effective in decreasing testosterone synthesis, resulting in significant antitumor effects in prostate cancer. Such treatments result in disruptions of complicated and intertwining pathways with systemic physiologic consequences via effects on the adrenal gland and renin-angiotensin-aldosterone axis. This review highlights some of these aspects that need to be taken into consideration when treating patients with androgen biosynthesis inhibitors. RECENT FINDINGS: Targeting CYP17A1, a key enzyme involved in androgen biosynthesis, is a well established treatment in prostate cancer. More recently, efforts are underway to target a gatekeeper enzyme of steroidogenesis, CYP11A1. This enzyme mediates conversion of cholesterol to pregnenolone, the first step in steroid hormone biogenesis. Studies are beginning to demonstrate antitumor effects of ODM-208, a CYP11A1 inhibitor in prostate cancer. Although anticipated to have a therapeutic role in prostate cancer, there are potential downstream effects of CYP11A1 targeting arising from suppression of the entire adrenal cortex, including long-term adrenal insufficiency and possibly cardiovascular dysregulation. SUMMARY: Agents targeting androgen biosynthesis can have systemic implications. Balancing management of prostate cancer with better understanding of the mechanisms associated with potential side effects will allow for patients to obtain improved antitumor benefit while mitigating against treatment-associated adverse effects.

Corneal Neurotization: Essentials for The Facial Paralysis Surgeon.

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

Gender differences in the surgical management of trachomatous trichiasis: an exploratory analysis of global trachoma survey data, 2015-2019.

BACKGROUND: Trachomatous trichiasis (TT) is a painful, potentially blinding eye condition that can be managed through epilation or surgery. Women are affected by TT approximately twice as often as men and are believed to face gendered barriers to receiving surgical care to prevent vision loss. METHODS: We used data from 817 cross-sectional surveys conducted during 2015-2019 in 20 African countries to estimate the prevalence difference (PD) between female and male eyes for four outcomes potentially indicating gender-related differences in TT management: (1) received surgery and developed postoperative TT (PTT), (2) never offered surgery, (3) offered surgery but declined it, and (4) offered epilation but never offered surgery. RESULTS: The prevalence was modestly elevated among female eyes compared with male eyes for having PTT (PD:1.8 [95% confidence limits (CL): 0.6, 3.0]) and having declined surgery for the eye (PD: 6.2 [95% CL: 1.8, 10.7]). The proportion offered epilation was similar by gender (PD:0.5 [95% CL: -0.4, 1.3]), while never having been offered surgery was somewhat more prevalent among male eyes (PD: -2.1 [95% CL: -3.5, -0.7]). CONCLUSIONS: Our results suggest potential gender differences in TT management. More research is needed to determine the causes and implications of the observed differences.

Prospects of earthworm coelomic fluid as a potential therapeutic agent to treat cancer.

Cancer is a major public health concern because it is one of the main causes of morbidity and mortality worldwide. As a result, numerous studies have reported the development of new therapeutic compounds with the aim of selectively treating cancer while having little negative influence on healthy cells. In this context, earthworm coelomic fluid has been acknowledged as a rich source of several bioactive substances that may exhibit promising anticancer activity. Therefore, the objective of the present review is to evaluate the findings of the reported studies exploring the antitumor effects of coelomic fluid in the context of its possible utilization as a natural therapeutic agent to cure different types of cancer. The possible mechanisms underlying the coelomic fluid's anticancerous potential as well as the possibility for future development of cutting-edge therapeutic agents utilizing coelomic fluid-derived natural bioactive compounds to treat cancer disorders have been discussed along with future challenges. In addition, the feasibility of encapsulation of bioactive compounds derived from coelomic fluid with nanomaterials that could be further explored to attain more effective anticancer competence is discussed.

Co-administration of Chrysin and Luteolin with Cisplatin and Topotecan Exhibits a Variable Therapeutic Value in Human Cancer Cells, HeLa.

Combinational treatment is a promising strategy for better cancer treatment outcomes. Chrysin and luteolin have demonstrated effective anticancer activity. Cisplatin and topotecan are commonly used for the treatment of human cancers. However, various side effects including drug resistance are an imperative restriction to use them as pharmacological therapy. Therefore, the aim was to use these agents in combination with flavones for better efficacy. In the present study, it was found that the combination of chrysin and cisplatin and luteolin and cisplatin significantly improved the anticancer effect as both the combinations showed synergistic interactions [combinational index (CI < 1)]. Remarkably, the combination of chrysin and luteolin with topotecan depicted the antagonistic interaction (CI > 1). Further, increased expression of the pro-apoptotic proteins Bax and caspase 8 and the inhibition of the antiapoptotic protein Bcl-2 were instituted in the synergistic doses (chrysin + cisplatin and luteolin + cisplatin), hence promoting apoptosis. Also, it was found that the synergistic combination inhibited the migration of HeLa cells by downregulation of metalloproteases and upregulation of TIMPs. However, there are no significant changes depicted in the antagonistic combinations which support their role in their antagonistic effects. Based on these results, it can be inferred that the two or more drug combinations need to be explored well for their interaction to enhance the therapeutic outcomes.

Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models.

BACKGROUND: Melittin is a water-soluble cationic peptide derived from bee venom that has been thoroughly studied for the cure of different cancers. However, the unwanted interactions of melittin produce hemolytic and cytotoxic effects that hinder their therapeutic applications. To overcome the shortcomings, numerous research groups have adopted different approaches, including conjugation with tumor-targeting proteins, gene therapy, and encapsulation in nanoparticles, to reduce the non-specific cytotoxic effects and potentiate their anti-cancerous activity. PURPOSE: This article aims to provide mechanistic insights into the chemopreventive activity of melittin and its nanoversion in combination with standard anti-cancer drugs for the treatment of cancer. METHODS: We looked over the pertinent research on melittin's chemopreventive properties in online databases such as PubMed and Scopus. CONCLUSION: In the present article, the anti-cancerous effects of melittin on different cancers have been discussed very nicely, as have their possible mechanisms of action to act against different tumors. Besides, it interacts with different signal molecules that regulate the diverse pathways of cancerous cells, such as cell cycle arrest, apoptosis, metastasis, angiogenesis, and inflammation. We also discussed the recent progress in the synergistic combination of melittin with standard anti-cancer drugs and a nano-formulated version of melittin for targeted delivery to improve its anticancer potential.

Metagenomic investigations on antibiotic resistance and microbial virulence in oil-polluted soils from China.

Engine oil spills have been associated with a wide range of human health problems. However, little is known about the effects of petroleum hydrocarbon pollution on soil microbial communities. In this study, three samples were collected from oil-polluted soils (OPS), and one control soil (CS) from Taolin town, China, near the old engine's scrapes was used. The aims of this study were to conduct metagenomic sequencing and subsequently perform resistome and virulome analysis. We also aimed to validate anti-microbial resistance and virulence genes and anti-bacterial sensitivity profiles among the isolates from oil-polluted soils. The OPS microbial community was dominated by bacterial species compared to the control samples which were dominated by metazoans and other organisms. Secondly, the resistosome and virulome analysis showed that ARGs and virulence factors were higher among OPS microbial communities. Antibiotic susceptibility assay and qPCR analysis for ARGs and virulence factors showed that the oil-polluted soil samples had remarkably enhanced expression of these ARGs and some virulence genes. Our study suggests that oil pollution contributes to shifting microbial communities to more resilient types that could survive the toxicity of oil pollution and subsequently become more resilient in terms of higher resistance and virulence potential.

Virulence traits and novel drug delivery strategies for mucormycosis post-COVID-19: a comprehensive review.

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk.

The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal.

The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.

Application of curcumin nanoformulations to target folic acid receptor in cancer: Recent trends and advances.

Curcumin, derived from turmeric, has a strong anticancer potential known for millennia. The development of this phytochemical as a medicine has been hampered by several significant deficiencies, including its poor water solubility and low bioavailability. This review article discusses possibilities to overcome these bottlenecks by focusing on this natural polyphenol's nanoformulation. Moreover, preparation of curcumin conjugates containing folates as ligands for folic acid receptors can add a new important dimension in this field, allowing specific targeting of cancer cells, considering the significantly higher expression of these receptors in malignant tissues compared to normal cells. It is highly expected that simultaneous improvement of different aspects of curcumin in fighting against such a complex and multifaceted disease like cancer. Therefore, we can better comprehend cancer biology by developing a mechanistic understanding of curcumin, which will also inspire the scientific community to develop new pharmacological models, and exploration of emerging directions to revitalize application of natural products in cancer therapy.

Case Report: COVID-19 Infection of a Transplanted Heart Simulating Cellular Rejection.

Contemporary reports showed that solid organ transplantation patients who contract SARS-CoV-2 infection have a high mortality rate. There are sparse data about recurrent cellular rejections and the immune response to the SARS-CoV-2 virus in patients after heart transplantation. Herein, we report a case of a 61-year-old male post-heart transplant patient who tested positive for COVID-19 and developed mild symptoms 4 months after transplantation. Thereafter, a series of endomyocardial biopsies showed histologic features of acute cellular rejection despite optimal immunosuppression, good cardiac functions, and hemodynamic stability. Demonstration of SARS-CoV-2 viral particles by electron microscopy in the endomyocardial biopsy confirmed the presence of the virus in the foci of the cellular rejection, pointing to a possible immunologic reaction to the virus. To our knowledge, there is limited information regarding the pathology of COVID-19 infection in immunocompromised heart transplant patients, and there are no well-established guidelines for treating such patients. Based on the demonstration of SARS-CoV-2 viral particles within the myocardium, we concluded that myocardial inflammation visible on endomyocardial biopsy might be attributed to the host's immune response to the virus, which mimics acute cellular rejection in newly heart transplanted patients. We report this case to increase awareness of such events post-transplantation and to add to knowledge regarding the management of patients with ongoing SARS-CoV-2 infection that proved to be challenging.

The interaction mechanism of plasma iron transport protein transferrin with nanoparticles.

In the biological systems, exposure to nanoparticles (NPs) can cause complicated interactions with proteins, the formation of protein corona and structural changes to proteins. These changes depend not only on NP physicochemical properties, but also on the intrinsic stability of protein molecules. Although, the formation of protein corona on the surface of NPs and the underlying mechanisms have been fully explored in various studies, no comprehensive review has discussed the direct biochemical and biophysical interactions between NPs and blood proteins, particularly transferrin. In this review, we first discussed the interaction of NPs with proteins to comprehend the effects of physicochemical properties of NPs on protein structure. We then overviewed the transferrin structure and its direct interaction with NPs to explore transferrin stability and its iron ion (Fe3+) release behavior. Afterwards, we surveyed the various biological functions of transferrin, such as Fe3+ binding, receptor binding, antibacterial activity, growth, differentiation, and coagulation, followed by the application of transferrin-modified NPs in the development of drug delivery systems for cancer therapy. We believe that this study can provide useful insight into the design and development of bioconjugates containing NP-transferrin for potential biomedical applications.

Electrochemical aptasensor based on the engineered core-shell MOF nanostructures for the detection of tumor antigens.

It is essential to develop ultrasensitive biosensors for cancer detection and treatment monitoring. In the development of sensing platforms, metal-organic frameworks (MOFs) have received considerable attention as potential porous crystalline nanostructures. Core-shell MOF nanoparticles (NPs) have shown different diversities, complexities, and biological functionalities, as well as significant electrochemical (EC) properties and potential bio-affinity to aptamers. As a result, the developed core-shell MOF-based aptasensors serve as highly sensitive platforms for sensing cancer biomarkers with an extremely low limit of detection (LOD). This paper aimed to provide an overview of different strategies for improving selectivity, sensitivity, and signal strength of MOF nanostructures. Then, aptamers and aptamers-modified core-shell MOFs were reviewed to address their functionalization and application in biosensing platforms. Additionally, the application of core-shell MOF-assisted EC aptasensors for detection of several tumor antigens such as prostate-specific antigen (PSA), carbohydrate antigen 15-3 (CA15-3), carcinoembryonic antigen (CEA), human epidermal growth factor receptor-2 (HER2), cancer antigen 125 (CA-125), cytokeratin 19 fragment (CYFRA21-1), and other tumor markers were discussed. In conclusion, the present article reviews the advancement of potential biosensing platforms toward the detection of specific cancer biomarkers through the development of core-shell MOFs-based EC aptasensors.

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE).

Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in metastatic castration-resistant prostate cancer (mCRPC). We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase I 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival, and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI; 100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLT) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% confidence interval, 27%-80%). Nine patients were evaluable for HRR gene status; 1 had a BRCA2 alteration (rPFS 11.8 months) and 1 had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200 mg orally twice daily with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase II study.

SMAD3 promotes expression and activity of the androgen receptor in prostate cancer.

Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ∼50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer.

Combined effect of ipilimumab and nivolumab improves oncology endpoints in metastatic melanoma patients.

Metastatic melanoma has less frequency, but considered as the most dreaded cancer. The combination of nivolumab & ipilimumab is proving their mettle in treating metastatic melanoma. The patients when administered with the combination of nivolumab & ipilimumab have shown improved median progression free survival, objective response rate and overall survival rate compared with nivolumab and ipilimumab monotherapy. The combination shrinks the tumor cells by attacking different checkpoints viz. CTLA-4 and PD-L1, respectively. The combination treatment reveals reduced disease progression and suggests nivolumab's non-cross resistant nature. The median progression free survival in "nivolumab plus ipilimumab" group has shown an increase of 66.7% and 296.6% in comparison to nivolumab and ipilimumab monotherapy. The other parameter viz. objective response rate improvement is equivalent to almost 14% and 38.6% when compared to nivolumab and ipilimumab monotherapy, respectively.

Ursolic acid: a pentacyclic triterpenoid that exhibits anticancer therapeutic potential by modulating multiple oncogenic targets.

The world is currently facing a global challenge against neoplastic diseases. Chemotherapy, hormonal therapy, surgery, and radiation therapy are some approaches used to treat cancer. However, these treatments are frequently causing side effects in patients, such as multidrug resistance, fever, weakness, and allergy, among others side effects. As a result, current research has focused on phytochemical compounds isolated from plants to treat deadly cancers. Plants are excellent resources of bioactive molecules, and many natural molecules have exceptional anticancer properties. They produce diverse anticancer derivatives such as alkaloids, terpenoids, flavonoids, pigments, and tannins, which have powerful anticancer activities against various cancer cell lines and animal models. Because of their safety, eco-friendly, and cost-effective nature, research communities have recently focused on various phytochemical bioactive molecules. Ursolic acid (UA) and its derivative compounds have anti-inflammatory, anticancer, apoptosis induction, anti-carcinogenic, and anti-breast cancer proliferation properties. Ursolic acid (UA) can improve the clinical management of human cancer because it inhibits cancer cell viability and proliferation, preventing tumour angiogenesis and metastatic activity. Therefore, the present article focuses on numerous bioactivities of Ursolic acid (UA), which can inhibit cancer cell production, mechanism of action, and modulation of anticancer properties via regulating various cellular processes.

Prophylactic lymphaticovenous anastomosis (LVA) for preventing lymphedema after sarcoma resection in the lower limb: A report of three cases and literature review.

Patients with soft tissue tumors of the lower extremities are at greater risk to develop postoperative disruption of lymphatic vessels. Currently, there is no widely effective cure for lymphatic dysfunction. Therefore, the best strategy is to prevent it and reconstruct efficient drainage as soon as the original pathway is damaged. We present a report of three prophylactic LVA cases after sarcoma resection in the lower limb, and a literature review to show the feasibility of prophylactic LVAs. The patients were 35, 73, and 77 years old, respectively, at the time of the procedure. All three patients had sarcoma in the medial thigh and underwent radiation therapy before the surgery. The locations of the LVAs include the medial thigh and medial and lateral calf. During the surgery, methylene blue and/or indocyanine green were injected to identify lymphatic vessels. Postoperative recovery was uneventful immediately after the surgery. At follow-up visits, all three patients reported improved functions with no significant swelling in the lower limb. One patient experienced a surgical wound infection that resolved after antibiotic admission. Two patients had a history of cardiac diseases, a major risk factor for developing postoperative lymphedema, but these two patients did not develop lymphedema with the treatment of prophylactic LVAs. These results suggest that prophylactic LVA may be an effective strategy to prevent secondary lymphedema after sarcoma resection. Further investigation is warranted.

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown. OBJECTIVE: To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib. DESIGN, SETTING, AND PARTICIPANTS: Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib. RESULTS AND LIMITATIONS: No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively). CONCLUSIONS: These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance. PATIENT SUMMARY: Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor-directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.