Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and

Discovery, TESS Characterization, and Modeling of Pulsations in the Extremely Low-mass White Dwarf GD 278

We report the discovery of pulsations in the extremely low-mass (ELM), likely helium-core white dwarf GD 278 via ground- and space-based photometry. GD 278 was observed by the Transiting Exoplanet Survey Satellite (TESS) in Sector 18 at a 2 minute cadence for roughly 24 days. The TESS data reveal at least 19 significant periodicities between 2447 and 6729 s, one of which is the longest pulsation period ever detected in a white dwarf. Previous spectroscopy found that this white dwarf is in a 4.61 hr orbit with an unseen >0.4 M ⊙ companion and has T eff = 9230 ± 100 K and logg=6.627±0.056" role="presentation">logg=6.627±0.056 , which corresponds to a mass of 0.191 ± 0.013 M ⊙. Patterns in the TESS pulsation frequencies from rotational splittings appear to reveal a stellar rotation period of roughly 10 hr, making GD 278 the first ELM white dwarf with a measured rotation rate. The patterns inform our mode identification for asteroseismic fits, which, unfortunately, do not reveal a global best-fit solution. Asteroseismology reveals two main solutions roughly consistent with the spectroscopic parameters of this ELM white dwarf, but with vastly different hydrogen-layer masses; future seismic fits could be further improved by using the stellar parallax. GD 278 is now the tenth known pulsating ELM white dwarf; it is only the fifth known to be in a short-period binary, but is the first with extended, space-based photometry.Fil: Lopez, Isaac D.. North Carolina State University; Estados UnidosFil: Hermes, J. J.. University Of Boston. Departament Astronomy; Estados UnidosFil: Calcaferro, Leila Magdalena. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Bell, Keaton. University of Washington; Estados UnidosFil: Samuels, Adam. University Of Boston. Departament Astronomy. Center For Space Physics; Estados UnidosFil: Vanderbosch, Zachary P.. University of Texas at Austin; Estados UnidosFil: Corsico, Alejandro Hugo. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Istrate, Alina G.. University of Utrecht; Países Bajo

Synchronous Symmetry Breaking in Neurons with Different Neurite Counts

As neurons develop, several immature processes (i.e., neurites) grow out of the cell body. Over time, each neuron breaks symmetry when only one of its neurites grows much longer than the rest, becoming an axon. This symmetry breaking is an important step in neurodevelopment, and aberrant symmetry breaking is associated with several neuropsychiatric diseases, including schizophrenia and autism. However, the effects of neurite count in neuronal symmetry breaking have never been studied. Existing models for neuronal polarization disagree: some predict that neurons with more neurites polarize up to several days later than neurons with fewer neurites, while others predict that neurons with different neurite counts polarize synchronously. We experimentally find that neurons with different neurite counts polarize synchronously. We also show that despite the significant differences among the previously proposed models, they all agree with our experimental findings when the expression levels of the proteins responsible for symmetry breaking increase with neurite count. Consistent with these results, we observe that the expression levels of two of these proteins, HRas and shootin1, significantly correlate with neurite count. This coordinated symmetry breaking we observed among neurons with different neurite counts may be important for synchronized polarization of neurons in developing organisms

Burden of child mortality from malaria in high endemic areas: results from the CHAMPS Network using minimally invasive tissue sampling

Background Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. Methods Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. Findings Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p<0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p=0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. Interpretation Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures. Funding This work was supported by the Bill & Melinda Gates Foundation [OPP1126780]

gyrA Mutations in Ciprofloxacin-Resistant Bartonella bacilliformis Strains Obtained In Vitro

We isolated and characterized mutants of Bartonella bacilliformis that are resistant to the fluoroquinolone antibiotic ciprofloxacin, which targets the A subunit of DNA gyrase. Mutants had single point mutations in the gyrA gene that changed either Asp-90 to Gly or Asp-95 to Asn and had 3- or 16-fold higher resistance, respectively, to ciprofloxacin than did wild-type B. bacilliformis. Asp-95 is homologous to Asp-87 of Escherichia coli GyrA and is a common residue mutated in fluoroquinolone-resistant strains of other bacteria. This is the first report of a mutation at an Asp-90 homologue, which corresponds to Asp-82 in E. coli GyrA

Beyond Presidentialism and Parliamentarism

The presidential-parliamentary distinction is foundational to comparative politics and at the center of a large theoretical and empirical literature. However, an examination of constitutional texts suggests a fair degree of heterogeneity within these categories with respect to important institutional attributes. These observations indicate that the classic presidential-parliamentary distinction, and the semipresidential category, may not be systemic. This article investigates whether the defining attributes that separate presidential and parliamentary constitutions predict other attributes that are stereotypically associated with these institutional models. The results suggest the need for considerable skepticism of the ‘systemic’ nature of the classification. Indeed, the results imply that in order to predict the powers of a country’s executive and legislature, it is more useful to know where and when the constitution was written than whether the country has a presidential or parliamentary system.Governmen