23 research outputs found
Outcomes and prognostic factors for women with breast cancer in Malawi
Background: Breast cancer incidence in sub-Saharan Africa (SSA) is increasing, and SSA has the highest age-standardized breast cancer mortality rate worldwide. However, high-quality breast cancer data are limited in SSA. Materials and Methods: We examined breast cancer patient and tumor characteristics among women in Lilongwe, Malawi and evaluated risk factor associations with patient outcomes. We consecutively enrolled 100 women ≥ 18 years with newly diagnosed, pathologically confirmed breast cancer into a prospective longitudinal cohort with systematically assessed demographic data, HIV status, and clinical characteristics. Tumor subtypes were further determined by immunohistochemistry, overall survival (OS) was estimated using Kaplan–Meier methods, and hazards ratios (HR) were calculated by Cox proportional hazard analyses. Results: Of the 100 participants, median age was 49 years, 19 were HIV-positive, and 75 presented with late stage (III/IV) disease. HER2-enriched and triple-negative/basal-like subtypes represented 17% and 25% tumors, respectively. One-year OS for the cohort was 74% (95% CI 62–83%). Multivariable analyses revealed mortality was associated with HIV (HR, 5.15; 95% CI 1.58–16.76; p = 0.006), stage IV disease (HR, 8.86; 95% CI 1.07–73.25; p = 0.043), and HER2-enriched (HR, 7.46; 95% CI 1.21–46.07; p = 0.031), and triple-negative subtypes (HR, 7.80; 95% CI 1.39–43.69; p = 0.020). Conclusion: Late stage presentation, HER2-enriched and triple-negative subtypes, and HIV coinfection were overrepresented in our cohort relative to resource-rich settings and were associated with mortality. These findings highlight robust opportunities for population- and patient-level interventions across the entire cascade of care to improve breast cancer outcomes in low-income countries in SSA
The L 98-59 System: Three Transiting, Terrestrial-size Planets Orbiting a Nearby M Dwarf
We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R ⊕ to 1.6 R ⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system
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Direct Evidence that the Arcuate Nucleus-Median Eminence Tuberoinfundibular System Is Not of Primary Importance in the Feedback Regulation of Luteinizing Hormone and Follicle-Stimulating Hormone Secretion in the Castrated Rat
Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain\u27s deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment
Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities
Several reports have recently emerged
regarding the identification
of heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. The
optimization of a series of internal Na<sub>V</sub>1.7 leads that
address a number of metabolic liabilities including bioactivation,
PXR activation, as well as CYP3A4 induction and inhibition led to
the identification of potent and selective inhibitors that demonstrated
favorable pharmacokinetic profiles and were devoid of the aforementioned
liabilities. The key to achieving this within a series prone to transporter-mediated
clearance was the identification of a small range of optimal cLogD
values and the discovery of subtle PXR SAR that was not lipophilicity
dependent. This enabled the identification of compound <b>20</b>, which was advanced into a target engagement pharmacodynamic model
where it exhibited robust reversal of histamine-induced scratching
bouts in mice