The recent development of immune-based therapies has improved the outcome for cancer patients; however, adjuvant therapies remain an important line of treatment for several cancer types. To maximize ...efficacy, checkpoint inhibitors are often combined with cytotoxic agents. While this approach often leads to increased tumor regression, higher off target toxicity often results in certain patients. This report describes a novel formulation comprising a unique amphiphilic molecule, 8-((2-hydroxybenzoyl)amino)octanoate (SHAO), that non-covalently interacts with payloads to increase drug dispersion and diffusion when dosed intratumorally (IT) into solid tumors. SHAO is co-formulated with cisplatin and vinblastine (referred to as INT230-6). IT dosing of the novel formulation achieved greater tumor growth inhibition and improved survival in in vivo tumor models compared to the same drugs without enhancer given intravenously or IT. INT230-6 treatment increased immune infiltrating cells in injected tumors with 10% to 20% of the animals having complete responses and developing systemic immunity to the cancer. INT230-6 was also shown to be synergistic with programmed cell death protein 1 (PD-1) antibodies at improving survival and increasing complete responses. INT230-6 induced significant tumor necrosis potentially releasing antigens to induce the systemic immune-based anti-cancer attack. This research demonstrates a novel, local treatment approach for cancer that minimizes systemic toxicity while stimulating adaptive immunity.
Strain engineering in semiconductor transistor devices has become vital in the semiconductor industry due to the ever-increasing need for performance enhancement at the nanoscale. Raman spectroscopy ...is a non-invasive measurement technique with high sensitivity to mechanical stress that does not require any special sample preparation procedures in comparison to characterization involving transmission electron microscopy (TEM), making it suitable for inline strain measurement in the semiconductor industry. Indeed, at present, strain measurements using Raman spectroscopy are already routinely carried out in semiconductor devices as it is cost effective, fast and non-destructive. In this paper we explore the usage of linearized radially polarized light as an excitation source, which does provide significantly enhanced accuracy and precision as compared to linearly polarized light for this application. Numerical simulations are done to quantitatively evaluate the electric field intensities that contribute to this enhanced sensitivity. We benchmark the experimental results against TEM diffraction-based techniques like nano-beam diffraction and Bessel diffraction. Differences between both approaches are assigned to strain relaxation due to sample thinning required in TEM setups, demonstrating the benefit of Raman for nondestructive inline testing.
In an effort to provide high-quality preschool education, policymakers are increasingly requiring public pre-school teachers to have at least a Bachelor's degree, preferably in early childhood ...education. Seven major studies of early care and education were used to predict classroom quality and children's academic outcomes from the educational attainment and major of teachers of 4-year-olds. The findings indicate largely null or contradictory associations, indicating that policies focused solely on increasing teachers' education will not suffice for improving classroom quality or maximizing children's academic gains. Instead, raising the effectiveness of early childhood education likely will require a broad range of professional development activities and supports targeted toward teachers' interactions with children.
Meningiomas are the most common intracranial tumors, predominantly affecting adults, with a higher incidence in female and elderly populations. Despite their prevalence, research on neurocognitive ...impairment in meningioma patients remains limited compared to intra-axial tumors such as gliomas. We conducted a comprehensive systematic review of the current literature on neurocognitive outcomes in meningioma patients pre- and post-surgery. Our review revealed significant disparities in reported neurocognitive outcomes, with prospective studies suggesting tumor-related factors as the primary contributors to postoperative deficits, while retrospective studies imply surgical intervention plays a significant role. Regardless of study design or specifics, most studies lack baseline preoperative neurocognitive assessments and standardized protocols for evaluating neurocognitive function. To address these gaps, we advocate for standardized neurocognitive assessment protocols, consensus on neurocognitive domains to be targeted in this population by tailored test batteries, and more prospective studies to elucidate correlations between tumor characteristics, patient attributes, surgical interventions, neurocognitive status, and planning for implementing tailored neurocognitive rehabilitation strategies early in the postoperative course which is crucial for achieving optimal long-term neurocognitive outcomes and enhancing patients' quality of life.
•New HAADF STEM scanning strategy scans large fields of view in atomic resolution subimages, that are used to estimate local strain.•A significant reduction in drift induced artefacts is ...obtained.•The strain precision is nearly independent of scan direction.•Wider field of view strain maps in comparison to HRSTEM.•Non-linear regression using sinusoidal harmonic model for strain analysis is used for high precision.
Lattice strain measurement of nanoscale semiconductor devices is crucial for the semiconductor industry as strain substantially improves the electrical performance of transistors. High resolution scanning transmission electron microscopy (HR-STEM) imaging is an excellent tool that provides spatial resolution at the atomic scale and strain information by applying Geometric Phase Analysis or image fitting procedures. However, HR-STEM images regularly suffer from scanning distortions and sample drift during image acquisition. In this paper, we propose a new scanning strategy that drastically reduces artefacts due to drift and scanning distortion, along with extending the field of view. It consists of the acquisition of a series of independent small subimages containing an atomic resolution image of the local lattice. All subimages are then analysed individually for strain by fitting a nonlinear model to the lattice images. The method allows flexible tuning of spatial resolution and the field of view within the limits of the dynamic range of the scan engine while maintaining atomic resolution sampling within the subimages. The obtained experimental strain maps are quantitatively benchmarked against the Bessel diffraction technique. We demonstrate that the proposed scanning strategy approaches the performance of the diffraction technique while having the advantage that it does not require specialized diffraction cameras.
Abnormal neurodevelopment has been widely reported in combined methylmalonic aciduria (MMA) and homocystinuria, cblC type (cblC disease), but neurodevelopmental phenotypes in cblC have not previously ...been systematically studied. We sought to further characterize developmental neurology in children with molecularly-confirmed cblC. Thirteen children at our center with cblC, born since implementation of expanded newborn screening in New York State, undertook standard-of-care evaluations with a pediatric neurologist and pediatric ophthalmologist. At most recent follow-up (mean age 50months, range 9–84months), of twelve children with early-onset cblC, three (25%) had a history of clinical seizures and two (17%) meet criteria for microcephaly. A majority of children had hypotonia and nystagmus. Twelve out of thirteen (92%) underwent neurodevelopmental evaluation (mean age 41months; range 9–76months), each child tested with standardized parental interviews and, where possible, age- and disability-appropriate neuropsychological batteries. All patients showed evidence of developmental delay with the exception of one patient with a genotype predictive of attenuated disease and near-normal biochemical parameters. Neurodevelopmental deficits were noted most prominently in motor skills, with relative preservation of socialization and communication skills. Nine children with early-onset cblC underwent magnetic resonance imaging and spectroscopy (MRI/MRS) at mean age of 47months (range 6–81months); common abnormalities included callosal thinning, craniocaudally short pons, and increased T2 FLAIR signal in periventricular and periatrial white matter. Our study further characterizes variable neurodevelopmental phenotypes in treated cblC, and provides insights into the etiopathogenesis of disordered neurodevelopment frequently encountered in cblC. Plasma homocysteine and MMA, routinely measured at clinical follow-up, may be poor predictors for neurodevelopmental outcomes. Additional data from large, prospective, multi-center natural history studies are required to more accurately define the role of these metabolites and others, as well as that of other genetic and environmental factors in the etiopathogenesis of the neurologic components of this disorder.
•Neurodevelopmental delay has been reported in cblC but is not well characterized.•Early-onset patients showed delays and are at risk of visual impairment.•Motor delays were prominent, with modest preservation of socialization skills.•Common MRI findings included thin corpus callosum and short pons.•Plasma homocysteine and MMA may be poor predictors of neurologic outcome.
This paper reports on 45-nm fin pitch strained p-type Ge gate-all-around devices fabricated on 300-mm SiGe strain-relaxed-buffers (SRB). By improving the process integration flow, excellent ...electrical performance is demonstrated: the <inline-formula> <tex-math notation="LaTeX">Q </tex-math></inline-formula> factor is increased to 25 as compared to our previous work, <inline-formula> <tex-math notation="LaTeX">I_{ \mathrm{\scriptscriptstyle ON}} = \textsf {500}~\mu \text{A}/ \mu \text{m} </tex-math></inline-formula> at <inline-formula> <tex-math notation="LaTeX">I_{ \mathrm{\scriptscriptstyle OFF}} = \textsf {100} </tex-math></inline-formula> nA/<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> is achieved, approaching the best published results on Ge finFETs. Good negative-bias temperature instability reliability is also maintained, thanks to the use of Si-cap passivation. The process flow developed for the fabrication of the single Ge nanowire (NW) is adapted and vertically stacked strained Ge NWs featuring 8-nm channel diameter are successfully demonstrated. A systematic analysis of the strain evolution is conducted on both single and double Ge NWs after the most challenging steps of the process integration flow: 1.7-GPa uniaxial-stress is demonstrated along the Ge wire, which originates from the lattice mismatch between the Ge source/drain and the Si 0.3 Ge 0.7 SRB.
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