The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

Automotive 2.1 µm Full-Depth Deep Trench Isolation CMOS Image Sensor with a 120 dB Single-Exposure Dynamic Range.

An automotive 2.1 µm CMOS image sensor has been developed with a full-depth deep trench isolation and an advanced readout circuit technology. To achieve a high dynamic range, we employ a sub-pixel structure featuring a high conversion gain of a large photodiode and a lateral overflow of a small photodiode connected to an in-pixel storage capacitor. With the sensitivity ratio of 10, the expanded dynamic range could reach 120 dB at 85 °C by realizing a low random noise of 0.83 e- and a high overflow capacity of 210 ke-. An over 25 dB signal-to-noise ratio is achieved during HDR image synthesis by increasing the full-well capacity of the small photodiode up to 10,000 e- and suppressing the floating diffusion leakage current at 105 °C.

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. METHODS: The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. RESULTS: DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. CONCLUSIONS: Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.

Internalization of Salmonella in Leafy Vegetables during Postharvest Conditions.

The consumption of fresh produce is increasing due to its role in promoting a healthy and balanced diet. However, this trend is accompanied by increased foodborne disease cases associated with pathogens such as Escherichia, Listeria, and Salmonella. Previous studies provided evidence that the internalization of foodborne pathogens in fresh produce may be a potential contamination route and may pose a public health risk. This study investigates the combination effects of storage temperature and humidity on Salmonella internalization in six types of leafy greens (iceberg lettuce, romaine lettuce, red lettuce, green onion, spinach, and kale) during the storage stage. The results indicated that temperature plays a critical role in Salmonella internalization, with higher concentrations observed in samples stored at 25 °C compared to those stored at 7 °C. The mean concentration of internalized Salmonella in the iceberg lettuce sample was the highest and that in the green onion sample was the lowest (iceberg lettuce > red lettuce > romaine lettuce > spinach > kale > green onion). Mist conditions also had an impact on internalization. The group treated with mist showed an increase in Salmonella internalization of about 10-30% rather than the group without mist treatment. This research emphasizes the importance of understanding the factors influencing bacterial internalization in fresh produce and highlights the need for proper storage conditions to minimize the risk of contamination and ensure food safety.

Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase.

We sought to investigate the utility of ebastine (EBA), a second-generation antihistamine with potent anti-metastatic properties, in the context of breast cancer stem cell (BCSC)-suppression in triple-negative breast cancer (TNBC). EBA binds to the tyrosine kinase domain of focal adhesion kinase (FAK), blocking phosphorylation at the Y397 and Y576/577 residues. FAK-mediated JAK2/STAT3 and MEK/ERK signaling was attenuated after EBA challenge in vitro and in vivo. EBA treatment induced apoptosis and a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f, suggesting that EBA targets BCSC-like cell populations while reducing tumor bulk. EBA administration significantly impeded BCSC-enriched tumor burden, angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Our findings suggest that EBA may represent an effective therapeutic for the simultaneous targeting of JAK2/STAT3 and MEK/ERK for the treatment of molecularly heterogeneous TNBC with divergent profiles. Further investigation of EBA as an anti-metastatic agent for the treatment of TNBC is warranted.

A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis.

Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.

Single-Component Hydrophilic Terpolymer Thin Film Systems for Imparting Surface Chemical Versatility on Various Substrates.

We demonstrate a single-component hydrophilic photocrosslinkable copolymer system that incorporates all critical functionalities into one chain. This design allows for the creation of uniform functional organic coatings on a variety of substrates. The copolymers were composed of a poly(ethylene oxide)-containing monomer, a monomer that can release a primary amine upon UV light, and a monomer with reactive epoxide or cyclic dithiocarbonate with a primary amine. These copolymers are easily incorporated into the solution-casting process using polar solvents. Furthermore, the resulting coating can be readily stabilized through UV light-induced crosslinking, providing an advantage for controlling the surface properties of various substrates. The photocrosslinking capability further enables us to photolithographically define stable polymer domains in a desirable region. The resulting copolymer coatings were chemically versatile in immobilizing complex molecules by (i) post-crosslinking functionalization with the reactive groups on the surface and (ii) the formation of a composite coating by mixing varying amounts of a protein of interest, i.e., fish skin gelatin, which can form a uniform dual crosslinked network. The number of functionalization sites in a thin film could be controlled by tuning the composition of the copolymers. In photocrosslinking and subsequent functionalizations, we assessed the reactivity of the epoxide and cyclic dithiocarbonate with the generated primary amine. Moreover, the orthogonality of the possible reactions of the presented reactive functionalities in the crosslinked thin films with complex molecules is assessed. The resulting copolymer coatings were further utilized to define a hydrophobic surface or an active surface for the adhesion of biological objects.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Early Standardized Uptake Value Reduction in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy.

PURPOSE: We investigated the treatment response and prognosis using the neutrophil-to-lymphocyte ratio (NLR) and standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in neoadjuvant settings. METHODS: Baseline NLR and maximum SUV (SUVmax) were retrospectively analyzed in 273 females with breast cancer who received neoadjuvant chemotherapy followed by surgery. Of these, 101 patients underwent 18F-FDG PET after 3-4 neoadjuvant chemotherapy cycles, which allowed the measurement of ΔSUVmax, an early reduction in SUVmax. NLR and early SUVmax reduction (ΔSUVmax) were classified as low and high, respectively, relative to the median values. RESULTS: The mean NLR was lower, and the mean ΔSUVmax was higher in patients with pathologic complete response (pCR) than in those with residual tumors. The ΔSUVmax was an independent variable associated with pCR. Furthermore, the high NLR group had poor recurrence-free survival (RFS) and overall survival. Among patients with ΔSUVmax data, high NLR (adjusted hazard ratio, 2.82; 95% confidence intervals [CI], 1.26-6.28; P = 0.016) and low ΔSUVmax (adjusted hazard ratio, 2.39; 95% CI, 1.07-5.34; P = 0.037) were independent prognostic factors for poor RFS. The categorization of the patients into four groups according to the combination of NLR and ΔSUVmax showed that patients with high NLR and low ΔSUVmax had significantly poorer RFS. CONCLUSION: Baseline NLR and ΔSUVmax were significantly associated with the prognosis of patients with breast cancer who received neoadjuvant chemotherapy. These results suggest that metabolic non-responders with defective immune systems have worse survival outcomes.

ß-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features.

BACKGROUND: The emergence of de novo or intrinsic trastuzumab resistance is exceedingly high in breast cancer that is HER2 positive and correlates with an abundant cancer stem cell (CSC)-like population. We sought to examine the capacity of ß-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells. METHODS: The effect of ß-escin on trastuzumab-resistant and -sensitive cell lines in vitro was evaluated for apoptosis, expression of HER2 family members, and impact on CSC-like properties. An in vivo model of trastuzumab-resistant JIMT-1 was used to examine the efficacy and toxicity of ß-escin. RESULTS: ß-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. Attenuation of CSC-related features by ß-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. ß-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, ß-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals. CONCLUSIONS: Taken together, our findings highlight ß-escin as a promising candidate for the treatment of trastuzumab-resistant HER2-positive breast cancers.

N-glycosylation of UNC93B1 at a Specific Asparagine Residue Is Required for TLR9 Signaling.

Toll-like receptors (TLRs) play critical roles in the first line of host defense against pathogens through recognition of pathogen-associated molecular patterns and initiation of the innate immune responses. The proper localization of TLRs in specific subcellular compartments is crucial for their ligand recognition and downstream signaling to ensure appropriate responses against pathogens while avoiding erroneous or excessive activation. Several TLRs, including TLR7 and TLR9 but not TLR4, depend on UNC93B1 for their proper intracellular localization and signaling. Accumulating evidence suggest that UNC93B1 differentially regulates its various client TLRs, but the specific mechanisms by which UNC93B1 controls individual TLRs are not well understood. Protein N-glycosylation is one of the most frequent and important post-translational modification that occurs in membrane-localized or secreted proteins. UNC93B1 was previously shown to be glycosylated at Asn251 and Asn272 residues. In this study, we investigated whether N-glycosylation of UNC93B1 affects its function by comparing wild type and glycosylation-defective mutant UNC93B1 proteins. It was found that glycosylation of Asn251 and Asn272 residues can occur independently of each other and mutation of neither N251Q or N272Q in UNC93B1 altered expression and localization of UNC93B1 and TLR9. In contrast, CpG DNA-stimulated TLR9 signaling was severely inhibited in cells expressing UNC93B1(N272Q), but not in cells with UNC93B1(N251Q). Further, it was found that glycosylation at Asn272 of UNC93B1 is essential for the recruitment of MyD88 to TLR9 and the subsequent downstream signaling. On the other hand, the defective glycosylation at Asn272 did not affect TLR7 signaling. Collectively, these data demonstrate that the glycosylation at a specific asparagine residue of UNC93B1 is required for TLR9 signaling and the glycosylation status of UNC93B1 differently affects activation of TLR7 and TLR9.

General circulation and global heat transport in a quadrupling CO2 pulse experiment.

To investigate the response of the general circulation and global transport of heat through both atmosphere and ocean to two-types of carbon dioxide removal scenario, we performed an earth system model experiment in which we imposed a pulse-type quadrupling of CO2 forcing for 50 years and a gradual peak-and-decline of four-time CO2 forcing. We found that the results from two experiments are qualitatively similar to each other. During the forcing-on period, a dominant warming in the upper troposphere over the tropics and on the surface at high latitudes led to a slowdown in the Hadley circulation, but the poleward atmospheric energy transport was enhanced due to an increase in specific humidity. This counteracted the reduction in poleward oceanic energy transport owing to the suppression of the meridional overturning circulation in both Hemispheres. After returning the original CO2 level, the hemispheric thermal contrast was reversed, causing a southward shift of the intertropical convergence zone. To reduce the hemispheric thermal contrast, the northward energy transports in the atmosphere and ocean surface were enhanced while further weakening of the global-scale Atlantic meridional overturning circulation led to southward energy transport in the deep ocean.

Early-Stage Defense Mechanism of the Cotton Aphid Aphis gossypii Against Infection With the Insect-Killing Fungus Beauveria bassiana JEF-544.

Aphis gossypii, commonly known as the cotton aphid, is a widely distributed pest of agricultural crops and acts as a vector for many serious plant viruses. Cotton aphid shows high resistance to chemical insecticides due to rapid rates of genetic diversity as a result of its short life cycle, seasonal migration, and host alteration. As an alternative, entomopathogenic fungi can be used to control cotton aphids in an environmentally sound manner. However, little is known about how cotton aphids respond to fungal infection. In this work, a new Beauveria bassiana strain JEF-544 (Bb JEF-544) was selected and isolated through bioassays with high virulence against cotton aphid. Early response of cotton aphid to Bb JEF-544 infection was analyzed at the transcriptome level. Infected aphids were collected two days after treatment at 25% lethal time (LT25), and total RNA of non-infected and Bb JEF-544-infected aphids was independently subjected to sequencing. Infected aphids showed significant up-regulation of the insect hormone biosynthesis pathway. Bursicon (Burs) and crustacean cardioactive peptide (CCAP) receptors involved in molting along with ecdysone synthesis were also strongly up-regulated in the aphid response to the fungal infection. In the immune response, melanization in the hemocoel was significantly up-regulated, while phagocytosis was less actively transcribed. In conclusion, cotton aphids protect themselves from Bb JEF-544 infection by activating the immune response including melanization and insect molting hormones to shed infected cuticles. In addition to describing the initial stages of Bb JEF-544 infection at the transcriptome level, this work provides potential treatment targets and insight into how fungal isolates can effectively be used to control this serious aphid species.

A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response.

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.

The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells.

N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.

Axillary response according to neoadjuvant single or dual human epidermal growth factor receptor 2 (HER2) blockade in clinically node-positive, HER2-positive breast cancer.

Incorporating dual human epidermal growth factor receptor 2 (HER2) blockade into neoadjuvant systemic therapy (NST) led to higher response in patients with HER2-positive breast cancer. However, axillary response to treatment regimens, including single or dual HER2 blockade, in patients with clinically node-positive breast cancer remains uncertain. Our study aimed to examine the pathologic axillary response according to the type of NST, that is, single or dual HER2 blockade. In our study, 546 patients with clinically node-positive, HER2-positive breast cancer who received NST followed by axillary surgery were retrospectively selected and divided into three groups: chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab. The primary outcome was the axillary pathologic complete response (pCR). Among 471 patients undergoing axillary lymph node dissection, the axillary pCR rates were 43.5%, 74.5% and 68.8% in patients who received chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab, respectively. There was no difference in axillary pCR rates between patients who received single or dual HER2 blockade (P = .379). Among patients receiving chemotherapy + trastuzumab, patients without breast pCR had the greatest risk for residual axillary metastases (relative risk, 9.8; 95% confidence interval, 3.2-14.9; P < .0001). In conclusion, adding trastuzumab to chemotherapy increased the axillary pCR rate in patients with clinically node-positive, HER2-positive breast cancer; furthermore, dual HER2-blockade with trastuzumab and pertuzumab did not elevate the axillary response compared with trastuzumab alone. Breast pCR could be a strong predictor for axillary pCR in clinically node-positive patients treated with HER2-targeting therapy.

Transcriptome Analysis of the Japanese Pine Sawyer Beetle, Monochamus alternatus, Infected with the Entomopathogenic Fungus Metarhizium anisopliae JEF-197.

The Japanese pine sawyer (JPS) beetle, Monochamus alternatus Hope (Coleoptera: Cerambycidae), damages pine trees and transmits the pine wilt nematode, Bursaphelenchus xylophilus Nickle. Chemical agents have been used to control JPS beetle, but due to various issues, efforts are being made to replace these chemical agents with entomopathogenic fungi. We investigated the expression of immune-related genes in JPS beetle in response to infection with JEF-197, a Metarhizium anisopliae isolate, using RNA-seq. RNA samples were obtained from JEF-197, JPS adults treated with JEF-197, and non-treated JPS adults on the 8th day after fungal treatment, and RNA-seq was performed using Illumina sequencing. JPS beetle transcriptome was assembled de novo and differentially expressed gene (DEG) analysis was performed. There were 719 and 1953 up- and downregulated unigenes upon JEF-197 infection, respectively. Upregulated contigs included genes involved in RNA transport, ribosome biogenesis in eukaryotes, spliceosome-related genes, and genes involved in immune-related signaling pathways such as the Toll and Imd pathways. Forty-two fungal DEGs related to energy and protein metabolism were upregulated, and genes involved in the stress response were also upregulated in the infected JPS beetles. Together, our results indicate that infection of JPS beetles by JEF-197 induces the expression of immune-related genes.

Relationship of the standard uptake value of 18F-FDG-PET-CT with tumor-infiltrating lymphocytes in breast tumors measuring ≥ 1 cm.

Evidence suggests that tumor cells and tumor-infiltrating lymphocytes (TILs) compete for glucose in the tumor microenvironment and that tumor metabolic parameters correlate with localized immune markers in several solid tumors. We investigated the relationship of the standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG-PET-CT) with stromal TIL levels in breast cancer. We included 202 patients who underwent preoperative 18F-FDG-PET-CT and had a tumor measuring ≥ 1 cm. Maximum SUV (SUVmax) was determined using 18F-FDG-PET-CT. Multiple logistic regression was used to identify factors related to high TIL levels (≥ 40%). All tumors were treatment naïve. A significant and weak correlation existed between continuous SUVmax and continuous TIL levels (p = 0.002, R = 0.215). Tumors with high SUVmax (≥ 4) had higher mean TIL levels than those with low SUVmax (< 4). In multivariable analysis, continuous SUVmax was an independent factor associated with high TIL levels; each 1-unit increment in SUVmax corresponded to an odds ratio of 1.14 (95% confidence interval: 1.01-1.29) for high TIL levels. Our study implies that SUV is associated with TILs in breast cancer and provides clinical evidence that elevated glucose uptake by breast tumors can predict the immune system-activated tumor micromilieu.

State population indices predict Asian American and Pacific Islander successful substance use treatment completion: An exploratory observational study.

Cultural capital is a known factor supporting success in substance use disorder (SUD) treatment. We investigated Asian American and Pacific Islander (AAPI) State population metrics in relation to SUD treatment completion for US clients from 2006-2017 (N = 5,404,374). Metrics that may signify greater available cultural capital were State AAPI Percentage, State AAPI Percent Change, and State AAPI Population. AAPI Percentage, AAPI Percent Change were positively associated, while AAPI Population was negatively associated with treatment completion (p < 0.001). Findings suggest treatment agencies in areas with low AAPI densities may improve outcomes by supporting AAPI community and cultural social networks.

The Role of Testosterone in Patients With Heart Failure: A Systematic Review.

The consequences of heart failure (HF) remain high despite treatment advances. Deficiency of the anabolic axes is common in HF and is associated with an increased risk of death and worsening functional status. Exogenous testosterone use has been shown to decrease vascular resistance and improve cardiac output. The objective of this systematic review was to assess the efficacy (mortality, hospitalization, cardiac function, and quality of life) and safety of testosterone in HF patients. The Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines were followed. Four electronic databases were searched from inception until November 30, 2019. The initial search yielded 1308 articles, and 10 randomized controlled trials with exogenous testosterone in patients with HF were included after exclusion criteria were applied. One study evaluated the impact of testosterone on mortality and HF hospitalization; no difference was observed compared with placebo. In 5 studies, testosterone use was associated with an improvement in walking distance. In 1 of the 2 studies that evaluated functional status, New York Heart Association class was improved. In 2 out of 4 studies, quality of life was improved with therapy. When reported, testosterone use was not associated with an increase in side effects. Overall, testosterone use has not been shown to reduce the risk of death or HF hospitalization, with inconsistent evidence on the impact of therapy on quality of life. Additional trials are needed before testosterone can be recommended. Patients with HF should receive guideline-directed medical therapy with the assurance that patients are receiving maximum tolerated doses.