Visible light mediated synthesis of 1,3-diarylated imidazo[1,5-a]pyridines via oxidative amination of C-H catalyzed by graphitic carbon nitride.

Graphitic carbon nitride (g-C3N4) as a novel heterogeneous catalyst is employed for the visible light-mediated synthesis of the imidazo[1,5-a]pyridines via the oxidative amination of C-H bond at room temperature without the need for any additional solvent. Extensive characterization of the catalyst was performed using techniques such as FT-IR, PXRD, TGA, SEM and EDX analysis. The optimized conditions enabled the successful and expeditious conversion of a wide range of substrates to imidazo[1,5-a]pyridines in good yields; a notable advantage of this catalyst being recyclability, as it can be reused for up to five cycles without significant loss of activity. This feature makes it suitable for gram-scale synthesis of imidazo[1,5-a]pyridines. Additionally, this approach offers several benefits from a green chemistry perspective as affirmed by its favorable green chemistry metrics (GCM), including low process mass intensity (PMI), low E-factor, high atom economy (AE), and good reaction mass efficiency (RME) relative to existing protocols. In addition, chemical yield (CY), mass intensity (MI), mass productivity (MP) and optimum efficiency were also calculated. This environmentally friendly method offers multiple advantages and represents a significant advancement in the synthesis of imidazo[1,5-a]pyridines.

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.

Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males-but not females-and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized-but fewer-α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.

A New Conformationally Symmetrical Calix[4]pyrrole Based Supramolecular System for Liquid Crystalline and Window Layer Solar Cell Applications.

The newly symmetrical liquid crystalline compounds (CPB1 -CPB4 ) based on calix[4]pyrrole as central rigid core are synthesized via esterification reaction. All the four functionalized compounds exhibit columnar hexagonal phase (Colh ) over a higher mesophase temperature range and further stabilized mesophase upto room temperature. The thermal behavior and optical texture are identified by using differential scanning calorimetry (DSC), Polarizing optical microscopy (POM) while the molecular organization of compound in mesogenic state by X-ray diffraction technique. The molecular system based on calix[4]pyrrole core with symmetrical nature exhibited columnar type self-assembly at room temperature. All these four supramolecules with different side spacer show higher thermal stability. Based upon the optimization, compound CPB2 has been further tested to implicate as optical window layer in thin films solar cell devices. The calix[4]pyrrole functionalized supramolecular liquid crystalline compound based thin films showed suitable transmittance, optical energy band gap together with absorbance and extinction coefficient. The linear dependence of current on the voltage demonstrated Ohmic behavior of the CPB2 films. The surface morphology to the developed samples designated nearly uniform deposition of the CPB2 thin films together with grain growth. The findings warrant suitability of the films to implicate these as an eco-friendly optical window layer in thin films based solar cells.

Thiacalixarene Appended Azo-based Supramolecular Systems: Self-assembly and Photo Tuning Reversible Liquid Crystalline Properties.

Four new azo-based supramolecular materials containing thiacalixarene core substituted by variable alkoxy groups (TFA1 -TFA4 ) have been designed and synthesized for the mesomorphic and photoswitching properties. The liquid crystalline behavior were accomplished by using DSC, POM, and XRD studies. All azo-based thiacalixarene based materials with short and higher chain length display columnar hexagonal mesophase with broad temperature range. The thermal behavior of all the materials was investigated by DSC and TGA study. The structural and conformational study of the lower rim functionalized materials was confirmed by using different techniques. These thiacalixarene moulded liquid crystalline compounds shows columnar self-assembly type behavior and higher thermal stability. The introduction of bi-substituted azo-ester network towards the lower rim of thiacalixarene core has impact on the electron delocalization and liquid crystalline properties. The photoswitching properties suggested cis and trans azo-isomerization under radiation of UV light and higher thermal back relaxation time. The mesogenic behaviour of compound TFA2 and TFA4 were demolished by the influence of cis and trans isomerization. The structure-property correlation is studied to understand the variation in mesogenic properties with the substitution of variable alkoxy side chain.

Calixarene Functionalized Supramolecular Liquid Crystals and Their Diverse Applications.

Liquid crystals are considered to be the fourth state of matter with an intermediate order and fluidity in comparison to solids and liquids. Calixarenes are among one of the most versatile families of building blocks for supramolecular chemistry due to their unique vaselike structure that can be chemically engineered to have different shapes and sizes. During the last few decades, calixarenes have drawn much attention in the field of supramolecular chemistry due to their diverse applications in the fields of ion and molecular recognition, ion-selective electrodes for catalysis, drug delivery, gelation, organic electronics and sensors, etc. Imbuing liquid crystallinity to the calixarene framework leads to functionalized calixarene derivatives with fluidity and order. Columnar self-assembly of such derivatives in particular enhance the charge migration along the column due to the 1D stacking due to the enhanced π-π overlap. Considering limited reports and reviews on this new class of calixarene based liquid crystals, a comprehensive account of the synthesis of calixarene liquid crystals along with their mesomorphic behavior and potential applications are presented in this review.

Self-assisting robot-assisted pulmonary lobectomy has favorable outcome compared to VATS lobectomy.

Background: Open and video-assisted thoracoscopic surgery (VATS) pulmonary lobectomy requires a skilled assistant to complete the operation. A potential benefit of a robot is to allow a surgeon to complete the operation autonomously. We sought to determine the safety of performing robotic-assisted pulmonary lobectomy with self-assistance. Methods: We performed a retrospective analysis of self-assisting robot-assisted lobectomy. We evaluated the intraoperative and postoperative outcomes. We compared the outcome to the propensity matched group of patients who had VATS lobectomy. We also compared them to published outcomes of robot-assisted lobectomy. Results: 95 patients underwent self-assisted lobectomies. The median age was 70 years old, predominately female (57%) and white (85%) with 90% of patients undergoing surgery for cancer. The median of estimated blood loss was 25 mL during the operation with no conversions to open thoracotomies. After the operation, 17% of patients had major postoperative complications with a median length of stay of 2 days. At thirty-day follow-up, the readmission rate was 6.5%, with a mortality of 0%. Compared to the propensity matched VATS lobectomy group, there was significantly less conversion to open surgery (n=0, 0% vs. n=10, 12.2%, P=0.002), less intraoperative blood transfusions (n=0, 0% vs. n=6, 7.3%, P=0.03), less any complications (n=20, 24.4% vs. n=41, 50%, P=0.003), and less median length of stay (2 days, IQR 2, 5 days vs. 4 day, IQR 3, 6 days, P<0.001) in the self-assisting robot lobectomy group. Compared to published outcomes of robot-assisted lobectomy, our series had significantly fewer conversions to open (P=0.03), shorter length of stay (P<0.001), more discharges to home (93.7%) without a difference in procedure time (P=0.38), overall complication rates (P=0.16) and mortality (P=0.62). Conclusions: Self-assistance using the robot technology during pulmonary lobectomy had few technical complications and acceptable morbidity, length of stay, and mortality. This group had favorable outcome compared to VATS lobectomy. The ability to self-assist during pulmonary lobectomy is an additional benefit of the robot technology compared to open and VATS lobectomy.

α-synucleinopathy exerts sex-dimorphic effects on the multipurpose DNA repair/redox protein APE1 in mice and humans.

Lewy body disorders are characterized by oxidative damage to DNA and inclusions rich in aggregated forms of α-synuclein. Among other roles, apurinic/apyrimidinic endonuclease 1 (APE1) repairs oxidative DNA damage, and APE1 polymorphisms have been linked to cases of Lewy body disorders. However, the link between APE1 and α-synuclein is unexplored. We report that knockdown or inhibition of APE1 amplified inclusion formation in primary hippocampal cultures challenged with preformed α-synuclein fibrils. Fibril infusions into the mouse olfactory bulb/anterior olfactory nucleus (OB/AON) elicited a modest decrease in APE1 expression in the brains of male mice but an increase in females. Similarly, men with Lewy body disorders displayed lower APE1 expression in the OB and amygdala compared to women. Preformed fibril infusions of the mouse OB/AON induced more robust base excision repair of DNA lesions in females than males. No fibril-mediated loss of APE1 expression was observed in male mice when the antioxidant N-acetylcysteine was added to their diet. These findings reveal a potential sex-biased link between α-synucleinopathy and APE1 in mice and humans. Further studies are warranted to determine how this multifunctional protein modifies α-synuclein inclusions and, conversely, how α-synucleinopathy and biological sex interact to modify APE1.

Intersection of Inorganic Chemistry and Nanotechnology for the Creation of New Cancer Therapies.

Since its discovery in 1965, the inorganic drug cisplatin has become a mainstay of cancer therapies and has inspired many platinum (Pt)-based compounds to solve various issues of toxicity and limitations associated with the original cisplatin. However, many of these drugs/prodrugs continue to be plagued by an array of side effects, limited circulation, and half-life and off-target effects. To solve this issue, we have constructed an array of platinum-based prodrugs on a Pt(IV) skeleton, which provides more favorable geometry and hydrophobicity, easier functionalization, and ultimately better targeting abilities. Each of these Pt(IV) prodrugs aims to either combine cisplatin with other agents for a combination therapeutic effect or improve the targeting of cisplatin itself, all for the more effective treatment of specific cancers. Our developed prodrugs include Platin-A, which combines cisplatin with the anti-inflammatory agent aspirin, Platin-M, which is functionalized with a mitochondria-targeting moiety, and Platin-B and Platin-Cbl, which combine cisplatin with components to combat cellular resistance to chemotherapy. At the same time, however, we recognize the crucial role of nanotechnology in improving the efficacy of cisplatin prodrugs and other inorganic compounds for the treatment of cancers. We describe several key benefits provided by nanomedicine that vastly improve the reach and utility of cisplatin prodrugs, including the ability of biodegradable polymeric nanoparticles (NPs) to deliver these agents with precision to the mitochondria, transport drugs across the blood-brain barrier, and target cisplatin prodrugs to specific cancers using various ligands. In addition, we highlight our progress in the engineering of innovative new polymers to improve the release patterns, pharmacokinetics, and dosages of cancer therapies. In this Account, we aim to describe the growing need for collaboration between the fields of inorganic chemistry and nanotechnology and how new advancements can not only improve on traditional chemotherapeutic agents but also expand their reach to entirely new subsets of cancers. In addition to detailing the design and principles behind our modifications of cisplatin and the efficacy of these new prodrugs against aggressive, cisplatin-resistant, or metastatic cancers, we also shed light on nanotechnology's essential role in protecting inorganic drugs and the human body from one another for more effective disease treatment without the off-target effects with which it is normally associated. We hope that this perspective into the important intersection between inorganic medicinal chemistry and nanotechnology will inspire future research on cisplatin prodrugs and other inorganic agents, innovative polymer and NP design, and the ways in which these two fields can greatly advance cancer treatment.

Inflammatory bowel disease induces inflammatory and pre-neoplastic changes in the prostate.

BACKGROUND: Inflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate. METHODS: Using clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability. RESULTS: A higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest. CONCLUSIONS: These data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.

Blending of Designer Synthetic Polymers to a Dual Targeted Nanoformulation for SARS-CoV-2 Associated Kidney Damage.

As the COVID-19 pandemic has continued to spread, studies have shown that hospitalized COVID-19 patients are at significant risk for developing acute kidney injury (AKI), which can cause increased morbidity, the need for dialysis treatment, chronic kidney diseases, and even death. In this paper, we present a proof-of-concept study for the utilization of combination therapeutic-loaded dual-targeted biodegradable nanoparticles (NPs) to treat concurrent AKI and COVID-19 in patients by delivering the therapeutics across the gut epithelial barrier and to the kidney, in order to lower the viral load as well as reduce the symptoms of AKI. Despite recent vaccination efforts and the end of the COVID-19 pandemic in sight, problems related to the long-term effects of COVID-19 will continue to persist, including impacts on patients suffering from AKI and other chronic renal conditions. Therefore, the dual-targeted blended polymeric NP developed in this study to treat concurrent COVID-19 infection and AKI is a useful proof-of-concept nanoplatform for future treatments of these complications.

Heat Shock Protein 70 as a Sex-Skewed Regulator of α-Synucleinopathy.

The role of molecular chaperones, such as heat shock protein 70 (Hsp70), is not typically studied as a function of biological sex, but by addressing this gap we might improve our understanding of proteinopathic disorders that predominate in one sex. Therefore, we exposed male or female primary hippocampal cultures to preformed α-synuclein fibrils in a model of early-stage Lewy pathology. We first discovered that two mechanistically distinct inhibitors of Hsp70 function increased phospho-α-synuclein+ inclusions more robustly in male-derived neurons. Because Hsp70 is released into extracellular compartments and may restrict cell-to-cell transmission/amplification of α-synucleinopathy, we then tested the effects of low-endotoxin, exogenous Hsp70 (eHsp70) in primary hippocampal cultures. eHsp70 was taken up by and reduced α-synuclein+ inclusions in cells of both sexes, but pharmacological suppression of Hsp70 function attenuated the inhibitory effect of eHsp70 on perinuclear inclusions only in male neurons. In 20-month-old male mice infused with α-synuclein fibrils in the olfactory bulb, daily intranasal eHsp70 delivery also reduced inclusion numbers and the time to locate buried food. eHsp70 penetrated the limbic system and spinal cord of male mice within 3 h but was cleared within 72 h. Unexpectedly, no evidence of eHsp70 uptake from nose into brain was observed in females. A trend towards higher expression of inducible Hsp70-but not constitutive Hsp70 or Hsp40-was observed in amygdala tissues from male subjects with Lewy body disorders compared to unaffected male controls, supporting the importance of this chaperone in human disease. Women expressed higher amygdalar Hsp70 levels compared to men, regardless of disease status. Together, these data provide a new link between biological sex and a key chaperone that orchestrates proteostasis.

Brain-Accumulating Nanoparticles for Assisting Astrocytes to Reduce Human Immunodeficiency Virus and Drug Abuse-Induced Neuroinflammation and Oxidative Stress.

Human neurotropic immunodeficiency virus (HIV) ingress into the brain and its subsequent replication after infection results in viral reservoirs in the brain. The infected cells include microglia, perivascular macrophages, and astrocytes. HIV-associated neurocognitive disorders (HAND) affect glial cells by activating microglia and macrophages through neuroinflammation, as well as astrocytes through mitochondrial dysfunctions and the onset of oxidative stress, impairing the ability of these cells to engage in neuroprotection. Furthermore, the risk of neuroinflammation associated with HAND is magnified by recreational drug use in HIV-positive individuals. Most of the therapeutic options for HIV cannot be used to tackle the virus in the brain and treat HAND due to the inability of currently available combination antiretroviral therapies (ARTs) and neuroprotectants to cross the blood-brain barrier, even if the barrier is partially compromised by infection. Here, we report a strategy to deliver an optimized antiretroviral therapy combined with antioxidant and anti-inflammatory neuroprotectants using biodegradable brain-targeted polymeric nanoparticles to reduce the burden caused by viral reservoirs in the brain and tackle the oxidative stress and inflammation in astrocytes and microglia. Through in vitro coculture studies in human microglia and astrocytes as well as an in vivo efficacy study in an EcoHIV-infected, methamphetamine-exposed animal model, we established a nanoparticle-based therapeutic strategy with the ability to treat HIV infection in the central nervous system in conditions simulating drug use while providing enhanced protection to astrocytes, microglia, and neurons.

It's all in the name: Does nomenclature for indolent prostate cancer impact management and anxiety?

BACKGROUND: Despite consensus guidelines, many men with low-grade prostate cancer are not managed with active surveillance. Patient perception of the nomenclature used to describe low-grade prostate cancers may partly explain this discrepancy. METHODS: A randomized online survey was administered to men without a history of prostate cancer, presenting a hypothetical clinical scenario in which they are given a new diagnosis of low-grade prostate cancer. The authors determined whether diagnosis nomenclature was associated with management preference and diagnosis-related anxiety using ratings given on a scale from 1 to 100, adjusting for participant characteristics through multivariable linear regression. RESULTS: The survey was completed by 718 men. Compared with Gleason 6 out of 10 prostate cancer, the term grade group 1 out of 5 prostate cancer was associated with lower preference for immediate treatment versus active surveillance (ß = -9.3; 95% CI, -14.4, -4.2; P < .001), lower diagnosis-related anxiety (ß = -8.3; 95% CI, -12.8, -3.8; P < .001), and lower perceived disease severity (ß = -12.3; 95% CI, -16.5, -8.1; P < .001) at the time of initial diagnosis. Differences decreased as participants received more disease-specific education. Indolent lesion of epithelial origin, a suggested alternative term for indolent tumors, was not associated with differences in anxiety or preference for active surveillance. CONCLUSIONS: Within a hypothetical clinical scenario, nomenclature for low-grade prostate cancer affects initial perception of the disease and may alter subsequent decision making, including preference for active surveillance. Disease-specific education reduces the differential impact of nomenclature use, reaffirming the importance of comprehensive counseling and clear communication between the clinician and patient.

Predictive model for growth of Clostridium perfringens during cooling of cooked pork supplemented with sodium chloride and sodium pyrophosphate.

A dynamic model was developed to predict growth of Clostridium perfringens in cooked ground pork supplemented with salt (0-3% wt/wt) and sodium pyrophosphate (0-0.3% wt/wt) under varying temperatures. C. perfringens (NCTC 8238, NCTC 8239, and NCTC 10240) spores were heat shocked, cooled, and inoculated into ground pork. Isothermal bacterial growth was quantified with variable salt and phosphate concentrations at temperatures ranging from 15 to 51 °C. The primary Baranyi model was fitted to all C. perfringens growth profiles and gave a satisfactory fit (R2 ≥ 0.85). A quadratic polynomial secondary model was developed (P < 0.0001) to predict the maximum specific growth rate as a function of temperature, salt, and phosphate concentrations (R2 = 0.93). A dynamic model was developed and validated using growth data retrieved from 7 published studies. Thirty three out of 44 predictions were within the acceptable prediction zone (-0.5 ≤ prediction error ≤ 1.0). The developed predictive model can be used to minimize the risk of C. perfringens in pork products supplemented with additives during cooling.

Cause of death during prostate cancer survivorship: A contemporary, US population-based analysis.

BACKGROUND: More than 3.6 million men in the United States harbor a diagnosis of prostate cancer (PCa). The authors sought to provide in-depth analyses of the causes of death for contemporary survivors. METHODS: The authors performed a population-based cohort study in the United States (2000-2016) to assess causes of death for men diagnosed with PCa stratified by demographics and tumor stage. Using general population data, they calculated standardized mortality ratios (SMRs) as observed-to-expected death ratios. RESULTS: In total, 752,092 men with PCa, including 200,302 who died (27%), were assessed. A total of 29,048 men with local/regional disease (17%) died of PCa, whereas more than 4-fold men died of other causes (n = 143,719 [83%]). SMRs for death from noncancer causes (0.77; 95% confidence interval [CI], 0.77-0.78) suggested that these men were less likely than the general population to die of most other causes. The most common noncancer cause of death was cardiac-related (23%; SMR, 0.76; 95% CI, 0.75-0.77). Among men with distant PCa, 90% of deaths occurred within 5 years of diagnosis. Although deaths due to PCa composed the majority of deaths (74%), SMRs suggested that men with distant PCa were at heightened risk for death from most other noncancer causes (1.50; 95% CI, 1.46-1.54) and, in particular, for cardiac-related death (SMR, 1.48; 95% CI, 1.41-1.54) and suicide (SMR, 2.32; 95% CI, 1.78-2.96). Further analyses demonstrated that causes of death varied by patient demographics. CONCLUSIONS: Causes of death during PCa survivorship vary by patient and tumor characteristics. These data provide valuable information regarding health care prioritization during PCa survivorship. LAY SUMMARY: Men with early-stage prostate cancer are 4-fold more likely to die of other causes, whereas those with advanced prostate cancer are at increased risk for several causes not related to prostate cancer in comparison with the general population. These findings can help guide physicians taking care of men with a diagnosis of prostate cancer.

A predictive growth model for Clostridium botulinum during cooling of cooked uncured ground beef.

A dynamic model to predict the germination and outgrowth of Clostridium botulinum spores in cooked ground beef was presented. Raw ground beef was inoculated with a ten-strain C. botulinum spore cocktail to achieve approximately 2 log spores/g. The inoculated ground beef was vacuum packaged, cooked to 71 °C to heat shock the spores, cooled to below 10 °C, and incubated isothermally at temperatures from 10 to 46 °C. C. botulinum growth was quantified and fitted into the primary Baranyi Model. Secondary models were fitted to maximum specific growth rate and lag phase duration using Modified Ratkowsky equation (R2 0.96) and hyperbolic function (R2 0.94), respectively. Similar experiments were also performed under non-isothermal (cooling) conditions. Acceptable zone prediction (APZ) analysis was conducted on growth data collected over 3 linear cooling regimes from the current study. The model performance (prediction errors) for all 22 validation data points collected in the current work were within the APZ limits (-1.0 to +0.5 log CFU/g). Additionally, two other growth data sets of C. botulinum reported in the literature were also subjected to the APZ analysis. In these validations, 20/22 and 10/14 predictions fell within the APZ limits. The model presented in this work can be employed to predict C. botulinum spore germination and growth in cooked uncured beef under non-isothermal conditions. The beef industry processors and food service organizations can utilize this predictive microbial model for cooling deviations and temperature abused situations and in developing customized process schedules for cooked, uncured beef products.

Survival following upfront chemotherapy for treatment-naïve metastatic prostate cancer: a real-world retrospective cohort study.

BACKGROUND: Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort. METHODS: We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis. RESULTS: After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemotherapy was associated with longer overall survival (hazard ratio 0.78, 95% confidence interval 0.68-0.89, p < 0.001). In exploratory analyses, the association between upfront chemotherapy and overall survival did not differ by age groups, race, or number of comorbidities (all interaction p > 0.2). CONCLUSIONS: In this real-world cohort, upfront chemotherapy for mHSPC was associated with longer overall survival. These data support the continued use of chemotherapy for men with mHSPC regardless of race or age if they are fit for chemotherapy and underscore the importance of evaluating cancer therapeutics outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.