Assessment of gender representation in clinical trials leading to FDA approval for oncology therapeutics between 2014 and 2019: A systematic review-based cohort study.

BACKGROUND: Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. METHODS: An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. RESULTS: There were 149 clinical trials with 59,988 participants-60.3% and 39.7% were male and female, respectively-leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, -26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). CONCLUSIONS: For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. LAY SUMMARY: This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

Application of the 3D digital ostectomy template (DOT) in mandibular angle ostectomy (MAO).

BACKGROUND: Mandibular angle ostectomy (MAO) is a standard approach in reconstruction of facial contour that is commonly used in East Asian patients with prominent mandibular angles (PMA). MAO is commonly performed via an intraoral approach to reduce scar visibility and risk of facial nerve injury. Since this intraoral approach for MAO has limited visual guidance during the procedure, plastic surgeons often perform the operation based on personal clinical experience. Therefore, we designed a 3D digital ostectomy template (DOT) for guidance during surgery to improve the accuracy and safety of MAO. METHODS: 10 female patients (average age 25.3 years) with PMA were enrolled in this study from August 2014 to October 2015. The DOTs were designed and printed preoperatively and utilized in the operation to guide the osteotomy. The excised mandibular angle bone and the DOTs were measured respective to each other. The data were analyzed to verify the feasibility and safety of the DOT. RESULTS: All of the patients were satisfied with the surgical results, and no complications such as fracture, hemorrhage and infection occurred. The distance from gonion (Go) along inferior margin of mandible forward to the distal end of the excised bone is "a". The distance from Go along posterior margin of ramus upward to the distal end of the excised bone is "b". The widest distance from Go to the ostectomy line is denoted by "c". Similarly, the corresponding distance in the DOT is denoted by "a'", "b'", "c'". The statistical results showed that left a vs a', b vs b', c vs c' was 63.27 ± 6.39 mm vs 62.97 ± 6.30 mm (p > 0.05), 23.98 ± 2.25 mm vs 21.83 ± 2.27 mm (p < 0.05), 13.58 ± 2.24 mm vs 13.37 ± 2.14 mm (p > 0.05), respectively. The right a vs a', b vs b', c vs c' was 62.92 ± 5.00 mm vs 62.72 ± 4.99 mm (p > 0.05), 24.03 ± 1.88 mm vs 21.80 ± 1.91 mm (p < 0.05), 13.36 ± 1.70 mm vs 13.22 ± 1.72 mm (p > 0.05), respectively. The results indicate a significant difference between b and b' both on the right and left sides. CONCLUSION: Through the application of DOT in MAO, the accuracy and safety of the operation were improved significantly. Unfortunately, the osteotomy could not be guided well in the posterior rim of the ramus. Further improvements in the surgical template are needed for application in PMA associated with oversized chin deformity or in PMA associated with large mandibular angle and severe involution.

NADPH oxidase 2 deletion enhances neurogenesis following traumatic brain injury.

The NADPH oxidase (NOX) enzyme family is a major source of reactive oxygen species (ROS) and contributor to the secondary pathology underlying traumatic brain injury (TBI). However, little is known about how NOX-derived ROS influences the proliferation and cell-fate determination of neural stem/progenitor cells (NSCs/NPCs) following TBI. In the current study, we found that deletion of NOX2 (NOX2-KO) significantly decreases the population of radial glia-like NSCs and neuroblasts but maintains the population of non-radial Sox2 expressing stem cells under physiological (non-injury) conditions. Surprisingly, the brains of NOX2-KO mice demonstrated a robust increase in the number of neuroblasts during the first week after TBI, as compared to the wild-type group. This increase may result from an enhanced proliferation of NPCs in a lower ROS environment after brain injury, as further examination revealed a significant increase of dividing neuroblasts in both NOX2-KO and NOX inhibitor-treated mouse brain during the first week following TBI. Finally, 5-Bromo-2'-deoxyuridine (BrdU) lineage tracing demonstrated a significantly increased number of newborn neurons were present in the perilesional cortex of NOX2-KO mice at 5 weeks post TBI, indicating that deletion of NOX2 promotes long-term neurogenesis in the injured brain following TBI. Altogether, these findings suggest that targeting NOX through genetic deletion or inhibition enhances post-injury neurogenesis, which may be beneficial for recovery following TBI.

NADPH oxidases in traumatic brain injury - Promising therapeutic targets?

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Despite intense investigation, no neuroprotective agents for TBI have yet translated to the clinic. Recent efforts have focused on identifying potential therapeutic targets that underlie the secondary TBI pathology that evolves minutes to years following the initial injury. Oxidative stress is a key player in this complex cascade of secondary injury mechanisms and prominently contributes to neurodegeneration and neuroinflammation. NADPH oxidase (NOX) is a family of enzymes whose unique function is to produce reactive oxygen species (ROS). Human post-mortem and animal studies have identified elevated NOX2 and NOX4 levels in the injured brain, suggesting that these two NOXs are involved in the pathogenesis of TBI. In support of this, NOX2 and NOX4 deletion studies have collectively revealed that targeting NOX enzymes can reduce oxidative stress, attenuate neuroinflammation, promote neuronal survival, and improve functional outcomes following TBI. In addition, NOX inhibitor studies have confirmed these findings and demonstrated an extended critical window of efficacious TBI treatment. Finally, the translational potential, caveats, and future directions of the field are highlighted and discussed throughout the review.

Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury.

Traumatic brain injury (TBI) contributes to over 30% of injury-related deaths and is a major cause of disability without effective clinical therapies. Oxidative stress contributes to neurodegeneration, neuroinflammation, and neuronal death to amplify the primary injury after TBI. NADPH oxidase (NOX) is a major source of reactive oxygen species following brain injury. Our current study addresses the functional role of the NOX4 isoform in the damaged cortex following TBI. Adult male C57BL/6 J and NOX4-/- mice received a controlled cortical impact and lesion size, NOX4 expression, oxidative stress, neurodegeneration, and cell death were assessed in the injured cerebral cortex. The results revealed that NOX4 mRNA and protein expression were significantly upregulated at 1-7 days post-TBI in the injured cerebral cortex. Expression of the oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine was upregulated at 2 and 4 days post-TBI in the WT injured cerebral cortex, and nitrotyrosine primarily colocalized with neurons. In the NOX4-/- mice, expression of these oxidative stress markers, 8-OHdG, 4-HNE, and nitrotyrosine were significantly attenuated at both timepoints. In addition, examination of NOX4-/- mice revealed a reduced number of apoptotic (TUNEL+) and degenerating (FJB+) cells in the perilesional cortex after TBI, as well as a smaller lesion size compared with the WT group. The results of this study implicate a functional role for NOX4 in TBI induced oxidative damage and neurodegeneration and raise the possibility that targeting NOX4 may have therapeutic efficacy in TBI.

Effect of myostatin deletion on cardiac and microvascular function.

The objective of this study is to test the hypothesis that increased muscle mass has positive effects on cardiovascular function. Specifically, we tested the hypothesis that increases in lean body mass caused by deletion of myostatin improves cardiac performance and vascular function. Echocardiography was used to quantify left ventricular function at baseline and after acute administration of propranolol and isoproterenol to assess ß-adrenergic reactivity. Additionally, resistance vessels in several beds were removed, cannulated, pressurized to 60 mmHg and reactivity to vasoactive stimuli was assessed. Hemodynamics were measured using in vivo radiotelemetry. Myostatin deletion results in increased fractional shortening at baseline. Additionally, arterioles in the coronary and muscular microcirculations are more sensitive to endothelial-dependent dilation while nonmuscular beds or the aorta were unaffected. ß-adrenergic dilation was increased in both coronary and conduit arteries, suggesting a systemic effect of increased muscle mass on vascular function. Overall hemodynamics and physical characteristics (heart weight and size) remained unchanged. Myostatin deletion mimics in part the effects of exercise on cardiovascular function. It significantly increases lean muscle mass and results in muscle-specific increases in endothelium-dependent vasodilation. This suggests that increases in muscle mass may serve as a buffer against pathological states that specifically target cardiac function (heart failure), the ß-adrenergic system (age), and nitric oxide bio-availability (atherosclerosis). Taken together, pharmacological inhibition of the myostatin pathway could prove an excellent mechanism by which the benefits of exercise can be conferred in patients that are unable to exercise.

Regulatory role of NADPH oxidase 2 in the polarization dynamics and neurotoxicity of microglia/macrophages after traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability. Secondary injuries that develop after the initial trauma contribute to long-lasting neurophysiological deficits. Polarization of microglia/macrophages toward a pro-inflammatory (M1) phenotype may increase the progression of secondary injury following TBI; however, the regulatory and functional mechanisms underlying these changes remain poorly defined. In the present study, we showed elevated expression of NADPH oxidase 2 (NOX2) and activation of nuclear factor-kappa B (NF-κB) predominantly in microglia/macrophages at 4- and 7-days after controlled cortical impact in mice. Delayed inhibition of NOX2, beginning one day after TBI, reduced reactive oxygen species production of myeloid cells and protected neurons from oxidative damage. Moreover, delayed NOX inhibition or global genetic NOX2 knockout suppressed the M1 "pro-inflammatory" profile of microglia/macrophages and simultaneously increased the M2 "anti-inflammatory" profile in the injured brain. These changes were associated with marked down-regulation of the classical NF-κB pathway in microglia/macrophages and reduced production of pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1ß, after TBI. Finally, we demonstrated that wild-type microglia/macrophages isolated from the ipsilateral cortex at 7 days post-TBI were neurotoxic to co-cultured primary neurons, whereas this neurotoxicity was largely attenuated in microglia/macrophages from NOX2-KO mice. Taken together, our study shows a direct link between NOX2 and the NF-κB pathway in microglia/macrophages after TBI, and it provides a novel mechanism by which NOX2 activation leads to the enhanced inflammatory response and neuronal damage after brain injury. Our data also supports the therapeutic potential of targeting NOX2, which may provide efficacy with an extended therapeutic window after TBI.

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1ß (IL-1ß), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

NADPH oxidase in brain injury and neurodegenerative disorders.

Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.