Abnormal global alternative RNA splicing in COVID-19 patients.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

Copper-catalyzed asymmetric 1,2-arylboration of enamines: access to chiral borate-containing 3,3'-disubstituted isoindolinones.

An enantioselective copper-catalyzed 1,2-arylboration reaction of enamines has been developed by employing (R)-xyl-BINAP as a chiral ligand. A number of chiral borate-containing 3,3'-disubstituted isoindolinones were obtained in moderate to good yields and good to excellent enantioselectivities from the reactions of N-(o-iodobenzoyl)enamines and bis(pinacolato)diboron (B2pin2) under mild reaction conditions. Synthetic transformations of the products were conducted to demonstrate the practicality of this reaction.

Nomogram predicting the efficacy of transurethral surgery in benign prostatic hyperplasia patients.

PURPOSE: This study aimed to develop and validate a nomogram for predicting the efficacy of transurethral surgery in benign prostatic hyperplasia (BPH) patients. METHODS: Patients with BPH who underwent transurethral surgery in the West China Hospital and West China Shang Jin Hospital were enrolled. Patients were retrospectively involved as the training group and were prospectively recruited as the validation group for the nomogram. Logistic regression analysis was utilized to generate nomogram for predicting the efficacy of transurethral surgery. The discrimination of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots were applied to evaluate the calibration of the nomogram. RESULTS: A total of 426 patients with BPH who underwent transurethral surgery were included in the study, and they were further divided into a training group (n = 245) and a validation group (n = 181). Age (OR 1.07, 95% CI 1.02-1.15, P < 0.01), the compliance of the bladder (OR 2.37, 95% CI 1.20-4.67, P < 0.01), the function of the detrusor (OR 5.92, 95% CI 2.10-16.6, P < 0.01), and the bladder outlet obstruction (OR 2.21, 95% CI 1.07-4.54, P < 0.01) were incorporated in the nomogram. The AUC of the nomogram was 0.825 in the training group, and 0.785 in the validation group, respectively. CONCLUSION: The nomogram we developed included age, the compliance of the bladder, the function of the detrusor, and the severity of bladder outlet obstruction. The discrimination and calibration of the nomogram were confirmed by internal and external validation.

[Focal therapy for prostate cancer: Progress in research].

Prostate cancer (PCa) is currently the second most common malignancy in men worldwide，and its incidence rate is on the rise. Most cases of PCa are treated by radical prostatectomy, but with the development of medical imaging and innovation in therapeutic theories and technology, focal therapy has shown better application prospects in the treatment of PCa. Compared with radical prostatectomy, focal therapy yields satisfactory results in terms of effectiveness and reduction of complications in addition to avoidance of overtreatment and treatment-related financial burden. This article reviews the strategies of focal therapy for PCa, including cryoablation, high-intensity focused ultrasound, irreversible electroporation, and photodynamic therapy, with an analysis of the clinical trials in recent years.

Aromatic π-Components for Enantioselective Heck Reactions and Heck/Anion-Capture Domino Sequences.

Olefin functionalization represents one of the most important synthetic transformations in organic synthesis. Over the past decades, palladium-catalyzed enantioselective Heck reactions, and Heck/anion-capture domino sequences through olefin carbopalladation followed by termination of the resulting alkyl-Pd species have been extensively developed. Extension of the coupling partners from classical olefins to other π-components would enable further advances and open new space in this field. Aromatics are important and easily available bulk chemicals. Dearomative transformation of endocyclic aromatic π-bonds via the Heck reaction pathway provides an efficient and straightforward route to structurally diverse alicyclic compounds. Nevertheless, major challenges for this transformation include aromaticity breaking and reactivity and selectivity issues.Recently, we have engaged in developing catalytic enantioselective dearomative Heck reactions and related domino reactions. A range of heteroarenes and naphthalenes have been employed as novel π-coupling partners in these reactions. Through dearomative migratory insertion of endocyclic aromatic C-C π-bonds followed by interception of the transient alkyl-Pd species, enantioselective Heck reactions, reductive Heck reactions, Heck/anion-capture difunctionalization reactions, and heteroarenyne cycloisomerization reactions have been established. Relying on ß-H elimination of the alkyl-Pd intermediate, we realized enantioselective dearomative Heck reactions with a range of aromatic partners, including heterocyclic indoles, pyrroles, furans, benzofurans, and more challenging carbocyclic naphthalenes. In order to avoid the utilization of organohalide electrophiles, heteroarenyne cycloisomerization reaction was developed by merging intermolecular alkyne hydropalladation with intramolecular dearomative Heck reaction. Cycloisomerization of alkyne-tethered indoles delivered chiral indolines in excellent enantioselectivities with 100% atom economy. On the other hand, Heck/anion-capture domino sequences were established through nucleophilic trapping of the alkyl-Pd intermediate. When HCO2Na was employed as a capturing reagent, the enantioselective dearomative reductive Heck reaction of indoles was realized. By employing other nucleophiles, including alkynes, N-sulfonylhydrazones, and organoboron reagents, we developed a series of dearomative difunctionalization reactions. Two vicinal stereocenters with excellent enantio- and diastereoselectivities were constructed in the corresponding Heck/Sonogashira, Heck/vinylation, and Heck/borylation reactions. Moreover, dearomative 1,4-diarylation of naphthalenes was developed through Heck/Suzuki domino reactions, in which competitive C-H arylation and the direct Suzuki reaction were almost fully inhibited in the presence of a spiro-phosphoramidite ligand.In this Account, we provide a panoramic view of our results since 2015 on enantioselective Heck reactions and related domino sequences by extending the coupling partners from classical olefins to aromatic systems. Investigations outlined in this Account established straightforward and efficient access to a variety of structurally diverse chiral heteropolycyclic molecules starting from simple and planar aromatic compounds.

Role of the heat shock protein family in chlorpromazine-induced cardiotoxicity.

Chlorpromazine (CPZ), a first-generation antipsychotic, is widely used in treating schizophrenia and other psychiatric disorders. However, CPZ is also associated with an increased likelihood of sudden cardiac death, and the underlying mechanisms remain unclear. In our study, we aimed to determine the CPZ-induced changes in some members of the heat shock protein family in rat hearts and further explore the possible mechanisms of CPZ-induced cardiotoxicity. Twenty-four Sprague Dawley rats were randomly divided into three groups (n = 8 per group): control, low dose (33.216 mg/kg) and high dose (94.211 mg/kg). CPZ administration induced hypothermia in rats. Pathological changes, including ischaemia and hypoxia, were observed in rat hearts. Furthermore, the serum levels of cardiac Troponin T (c-TN-T) and brain natriuretic peptide (BNP) were elevated in the CPZ-exposed groups. Meanwhile, the protein and gene expression of HSP70, HSP60, HSP27 and HSP10 significantly differed between the CPZ-exposed and control groups. We conclude that acute CPZ exposure could lead to myocardial injury in rats, in which HSPs might play a crucial role. Further investigations are required to elucidate the underlying mechanisms.

Enantioselective Dearomative [3 + 2] Umpolung Annulation of N-Heteroarenes with Alkynes.

Enantioselective [3 + 2] annulation of N-heteroarenes with alkynes has been developed via a cobalt-catalyzed dearomative umpolung strategy in the presence of chiral ligand and reducing reagent. A variety of electron-deficient N-heteroarenes, including quinolines, isoquinolines, quinoxaline, and pyridines, and internal or terminal alkynes are employed in this reaction, showing a broad substrate scope and good functionality tolerance. Annulation of electron-rich indoles with alkynes is also developed. This protocol provides a straightforward access to a variety of N-spiroheterocyclic molecules in excellent enantioselectivities (76 examples, up to 99% ee).

[Advances in the study of vasovasostomy under the microscope].

Approximately 10－15% of the cases of male infertility worldwide are caused by obstructive azoospermia. Vasovasostomy (VV) is a gold-standard treatment of this disease, but the success rate of conventional VV remains low for failure to anastomose the vas deferens accurately. Fortunately, microscopy makes the field of vision clearer and greatly increases the success rate of vas deferens recanalization and pregnancy. VV under the microscope, including microsurgical VV, robot-assisted microsurgical VV, and laparoscope-assisted microsurgical VV, is of great importance for the treatment of male infertility. This article reviews the progress in the study of VV under the microscope.

[Advances in the genetic diagnosis and treatment of prostate cancer].

As the incidence of prostate cancer (PCa) increases with the aging of men, more and more attention is paid to the prevention and treatment of the pregnancy. In addition to widely used PSA test, MRI and other diagnostic strategies, PCa-related gene screening, with the development of such new technologies as second-generation gene sequencing, is more and more applied in the detection of PCa. Different types of tumor-related genes have different effects on the development and progression of PCa as well as different values in the diagnosis, treatment and prognosis of the malignancy. This review focuses on the advances in the studies of PCa-related critical genes and key gene pathways.

Identification of a lncRNA prognostic signature-related to stem cell index and its significance in colorectal cancer.

Background: The relationship between long noncoding RNAs (lncRNAs) and the mRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAs and their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

Lay abstract Previous evidence has indicated that the mRNA stem index (mRNAsi) is representative of the stemness of cancer stem cells (CSCs), whereas long noncoding RNAs (lncRNAs) may be crucial regulators in CSC phenotype. Nevertheless, the relationship between lncRNAs and mRNAsi in CRC is still unclear. Our results show that the mRNAsi was negatively related to pathological features and positively related to prognosis in CRC. Five mRNAsi-related lncRNAs were further identified and developed as a prognostic signature that could independently predict survival in CRC patients due to the five mRNAsi-related lncRNAs being involved in several pathways of CSCs and malignant cancer cell phenotypes, indicating the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

[Mechanisms of drug resistance in endocrinotherapy for castration-resistant prostate cancer].

Androgen plays a significant role in the development and progression of prostate cancer (PCa), one of the commonest malignancies in the male urogenital system. Castration-resistant PCa (CRPC) is the end-result of the majority of prostate cancer cases treated by androgen deprivation therapy (ADT). Furthermore, the androgen axis is reactivated due to adaptive intratumoral androgen biosynthesis, which can be driven by adrenal androgens and /or by changes in the androgen receptor (AR) including AR gene amplification. At present, drugs targeting the androgen axis, such as abiraterone and enzalutamide, et al, are used for the first-line therapy for CRPC. Nevertheless, drug resistance and disease progression occur during the treatment of CRPC by anti-androgen therapy. Therefore, an insight into the mechanisms of drug resistance in anti-androgen therapy for CRPC may help surmount the drug reistance and improve the prognosis of the malignancy.

Palladium-Catalyzed Enantioselective Heteroarenyne Cycloisomerization Reaction.

The extensively developed ene-type enantioselective cycloisomerization of classical 1,n-enynes provides an efficient approach to chiral cyclic 1,4-dienes. In contrast, the catalytic asymmetric heteroarenyne (heteroarene-alkyne) cycloisomerization involving the dearomative transformation of endocyclic aromatic C=C bonds remains unknown. Herein, we communicate a PdH-catalyzed enantioselective heteroarenyne cycloisomerization reaction of alkyne-tethered indole substrates (formal 1,5- and 1,6-enynes). Based on this strategy, a variety of structurally diverse chiral spiro and fused indoline derivatives bearing quaternary stereocenters and exocyclic C=C bonds are afforded in moderate to excellent yields and excellent enantioselectivities (up to 98 % ee). The classical ene-type enantioselective 1,5-enyne cycloisomerization of N-vinylpropiolamides is also developed to afford chiral 2-pyrrolones in good to excellent ee values.

Functional Characterization and Structural Basis of an Efficient Di-C-glycosyltransferase from Glycyrrhiza glabra.

A highly efficient di-C-glycosyltransferase GgCGT was discovered from the medicinal plant Glycyrrhiza glabra. GgCGT catalyzes a two-step di-C-glycosylation of flopropione-containing substrates with conversion rates of >98%. To elucidate the catalytic mechanisms of GgCGT, we solved its crystal structures in complex with UDP-Glc, UDP-Gal, UDP/phloretin, and UDP/nothofagin, respectively. Structural analysis revealed that the sugar donor selectivity was controlled by the hydrogen-bond interactions of sugar hydroxyl groups with D390 and other key residues. The di-C-glycosylation capability of GgCGT was attributed to a spacious substrate-binding tunnel, and the G389K mutation could switch di- to mono-C-glycosylation. GgCGT is the first di-C-glycosyltransferase with a crystal structure, and the first C-glycosyltransferase with a complex structure containing a sugar acceptor. This work could benefit the development of efficient biocatalysts to synthesize C-glycosides with medicinal potential.

Exosomes overexpressing miR-34c inhibit malignant behavior and reverse the radioresistance of nasopharyngeal carcinoma.

BACKGROUND: Malignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs. METHODS: Potentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology. RESULTS: The expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting ß-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or ß-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells. CONCLUSION: miR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

Adult primary testicular lymphoma: clinical features and survival in a series of patients treated at a high-volume institution in China.

BACKGROUND: To retrospectively investigate the clinical characteristics, initial treatment, relapse, therapy outcome, and prognosis of Chinese patients with primary testicular lymphoma (PTL) through analysis of the cases of our institute. METHODS: From December 2008 to July 2018, all patients with PTL were included in this study. Kaplan-Meier method was used to estimate PFS and OS. The Cox proportional hazards model was used to compare the survival times for groups of patients differing in terms of clinical and laboratory parameters. RESULTS: All 28 PTL patients (24 DLBCL, three NK/T lymphomas, and one Burkkit's lymphoma) with a median age of 65.5 years were included in this study. Six patients were observed recurrence among all the 22 individuals evaluated. Following orchiectomy and systemic chemotherapy, with or without intrathecal prophylaxis, complete response was achieved in 15 (68%) patients. For DLBCL patients, the median progression-free survival (PFS) was 44.63 months (95% CI 17.71-71.56 months), and the median overall survival (OS) was 77.02 months (95% CI, 57.35-96.69 months). For all the DLBCL patients, the 5-year PFS and 5-year OS were 35.4% (95%CI, 14.8-56.0%) and 53.4% (95%CI, 30.1-76.7%). Without further chemotherapy following orchiectomy (HR = 3.4, P = 0.03) were associated with inferior PFS of DLBCL patients. Advanced Ann Arbor stage (HR =5.9, P = 0.009) and high (international prognostic index, IPI) score: 3-5 (HR =3.9, P = 0.04) were correlated with shorter OS of DLBCL patients. CONCLUSION: This study confirms that PTL is an aggressive malignant with a poor prognosis. Limited Ann Arbor stage, further chemotherapy following orchiectomy, and low IPI score (less than 2) are correlated with superior survival for DLBCL patients.

TF3P: Three-Dimensional Force Fields Fingerprint Learned by Deep Capsular Network.

Molecular fingerprints are the workhorse in ligand-based drug discovery. In recent years, an increasing number of research papers reported fascinating results on using deep neural networks to learn 2D molecular representations as fingerprints. It is anticipated that the integration of deep learning would also contribute to the prosperity of 3D fingerprints. Here, we unprecedentedly introduce deep learning into 3D small molecule fingerprints, presenting a new one we termed as the three-dimensional force fields fingerprint (TF3P). TF3P is learned by a deep capsular network whose training is in no need of labeled data sets for specific predictive tasks. TF3P can encode the 3D force fields information of molecules and demonstrates the stronger ability to capture 3D structural changes, to recognize molecules alike in 3D but not in 2D, and to identify similar targets inaccessible by other 2D or 3D fingerprints based on only ligands similarity. Furthermore, TF3P is compatible with both statistical models (e.g., similarity ensemble approach) and machine learning models. Altogether, we report TF3P as a new 3D small molecule fingerprint with a promising future in ligand-based drug discovery. All codes are written in Python and available at https://github.com/canisw/tf3p.

Transurethral resection of ejaculatory duct combined with seminal vesiculoscopy for management of persistent or recurrent hemospermia in men with ejaculatory duct obstruction.

BACKGROUND: Persistent or recurrent haemospermia often occurs in individuals with ejaculatory duct obstruction (EDO). This study aimed to evaluate the efficacy and safety of transurethral resection of the ejaculatory duct (TURED) combined with seminal vesiculoscopy in treating persistent or recurrent haemospermia in men with EDO. METHODS: From June 2014 to March 2018, 103 consecutive patients with EDO who underwent TURED combined with seminal vesiculoscopy for persistent or recurrent haemospermia at the Department of Urology of West China Hospital were enrolled into this retrospective study. The patients were evaluated mainly by detailed history-taking and performing semen analysis, transrectal ultrasonography, and magnetic resonance imaging. RESULTS: Among the 103 patients, 79 (76.70%) had cysts of the lower male genitourinary tract; 63 (61.17%) had blood clots; and 32 (31.07%) had calculi in the seminal vesicle and/or prostatic utricle. The duration of postoperative follow-up was 12 months, and the symptoms of haemospermia disappeared in 96 (93.20%) patients. There was no significant difference in the semen PH and sperm count before and after surgery; however, the ejaculate volume and sperm motility significantly improved postoperatively. Except for two cases of acute urinary retention and one case of watery ejaculate after surgery, no severe postoperative complications, including epididymitis, urethral stricture, urinary incontinence, retrograde ejaculation, or rectal injury, were observed. CONCLUSION: TURED combined with seminal vesiculoscopy is a suitable method for the diagnosis and treatment of persistent or recurrent haemospermia in men with EDO.

Molecular biomarkers of cantharidin-induced cardiotoxicity in Sprague-Dawley rats: Troponin T, vascular endothelial growth factor and hypoxia inducible factor-1α.

Early diagnosis of cantharidin-induced myocardial injury is the key to reduce the fatality rate in clinical practice. The purpose of the present study was to explore biomarkers that can be used for the prediction and diagnosis of cantharidin-induced myocardial injury. Of 65 male Sprague-Dawley rats weighing 200-230 g, 25 rats were divided into five groups according to the administration dose of cantharidin (0, 1.34, 2.67, 4 and 5.34 mg/kg; n = 5 per group) and the other 40 rats were treated with 2.67 mg/kg cantharidin and divided into nine groups according to the administration time (0, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours; n = 4 per group). Pathological changes of hypoxia, necrosis and inflammation were confirmed in heart samples that were exposed to cantharidin by hematoxylin-eosin staining and overall scores of pathological changes among heart samples in cantharidin exposure groups showed an increasing trend compared with in the control group. Coexpression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α) and caspase9 was shown in the myocardium by immunofluorescence staining. Western blotting results showed that expression of VEGF, HIF-1α and caspase9 in cantharidin-treated rat hearts showed an increasing trend compared with in the control group. Results of enzyme-linked immunosorbent assay suggested that plasma levels of troponin T (TN-T), VEGF and HIF-1α were elevated at different intervals after cantharidin administration, and VEGF and HIF-1α had a significant linear relationship with TN-T that was verified by multiple linear regression analysis. Preliminary results serve to illustrate that TN-T, VEGF and HIF-1α might be valuable molecular markers in cantharidin-induced myocardial injury and that diagnostic accuracy needs to be studied further.

IL-8 protects prostate cancer cells from GSK-3ß-induced oxidative stress by activating the mTOR signaling pathway.

INTRODUCTION: Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation; however, the mechanisms underlying these processes remain unclear. Thus, we selected interleukin-8 (IL-8) as the bridge between inflammation and cancer cell oxidative stress-induced death and aimed to confirm its connection with mTOR and Glycogen synthase kinase-3 beta (GSK-3ß). METHODS: We overexpressed GSK-3ß and observed its effect on reactive oxygen species (ROS) and oxidative stress-induced cell death. IL-8 was then upregulated or downregulated to determine its impact on preventing cell damage due to GSK-3ß-induced oxidative stress. In addition, we overexpressed or knocked down mTOR to confirm its role in this process. Real-time PCR, Western blotting, transcription, Cell Counting Kit 8 (CCK-8), and flow cytometry analyses were performed in addition to the use of other techniques. RESULTS: IL-8 promotes prostate cancer cell proliferation and decreases apoptosis, whereas GSK-3ß activates the caspase-3 signaling pathway by increasing ROS and thereby induces oxidative stress-mediated cell death. In addition, mTOR can also decrease activation of the caspase-3 signaling pathway by inhibiting GSK-3 and thus decreasing ROS production. Moreover, the inhibitory effect of IL-8 on GSK-3ß occurs through the regulation of mTOR. CONCLUSION: The results of this study highlight the importance of GSK-3ß, which increases the production of ROS and thereby induces oxidative stress in tumor cells, whereas IL-8 and mTOR attenuate oxidative stress to protect prostate cancer cells through inhibition of GSK-3ß.

First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis.

BACKGROUND: The relationship between first-degree family history of female breast cancer and prostate cancer risk in the general population remains unclear. We performed a meta-analysis to determine the association between first-degree family history of female breast cancer and prostate cancer risk. METHODS: Databases, including MEDLINE, Embase, and Web of Science, were searched for all associated studies that evaluated associations between first-degree family history of female breast cancer and prostate cancer risk up to December 31, 2018. Information on study characteristics and outcomes were extracted based on the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. The quality of evidence was assessed using the GRADE approach. RESULTS: Eighteen studies involving 17,004,892 individuals were included in the meta-analysis. Compared with no family history of female breast cancer, history of female breast cancer in first-degree relatives was associated with an increased risk of prostate cancer [relative risk (RR) 1.18, 95% confidence interval (CI) 1.12-1.25] with moderate-quality evidence. A history of breast cancer in mothers only (RR 1.19, 95% CI 1.10-1.28) and sisters only (RR 1.71, 95% CI 1.43-2.04) was associated with increased prostate cancer risk with moderate-quality evidence. However, a family history of breast cancer in daughters only was not associated with prostate cancer incidence (RR 1.74, 95% CI 0.74-4.12) with moderate-quality evidence. A family history of female breast cancer in first-degree relatives was associated with an 18% increased risk of lethal prostate cancer (95% CI 1.04-1.34) with low-quality evidence. CONCLUSIONS: This review demonstrates that men with a family history of female breast cancer in first-degree relatives had an increased risk of prostate cancer, including risk of lethal prostate cancer. These findings may guide screening, earlier detection, and treatment of men with a family history of female breast cancer in first-degree relatives.