Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism.

Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

High-throughput feedback-enabled optogenetic stimulation and spectroscopy in microwell plates.

The ability to perform sophisticated, high-throughput optogenetic experiments has been greatly enhanced by recent open-source illumination devices that allow independent programming of light patterns in single wells of microwell plates. However, there is currently a lack of instrumentation to monitor such experiments in real time, necessitating repeated transfers of the samples to stand-alone analytical instruments, thus limiting the types of experiments that could be performed. Here we address this gap with the development of the optoPlateReader (oPR), an open-source, solid-state, compact device that allows automated optogenetic stimulation and spectroscopy in each well of a 96-well plate. The oPR integrates an optoPlate illumination module with a module called the optoReader, an array of 96 photodiodes and LEDs that allows 96 parallel light measurements. The oPR was optimized for stimulation with blue light and for measurements of optical density and fluorescence. After calibration of all device components, we used the oPR to measure growth and to induce and measure fluorescent protein expression in E. coli. We further demonstrated how the optical read/write capabilities of the oPR permit computer-in-the-loop feedback control, where the current state of the sample can be used to adjust the optical stimulation parameters of the sample according to pre-defined feedback algorithms. The oPR will thus help realize an untapped potential for optogenetic experiments by enabling automated reading, writing, and feedback in microwell plates through open-source hardware that is accessible, customizable, and inexpensive.

Nesidioblastosis with delayed diagnosis and post-operative complications in a patient with complex psychiatric history.

Nesidioblastosis is a rare condition of organic persistent hyperinsulinaemic hypoglycaemia, with fewer than 100 cases since it was first recorded. However, an increasing prevalence suggests previous underdiagnosis due to poor knowledge and awareness. This case describes the presentation, clinical decision-making and unique challenges in diagnosis and care of a 21-year-old female with nesidioblastosis and extensive psychiatric comorbidities. She was repeatedly misdiagnosed until 2021, despite having presented to emergency departments with hypoglycaemic symptoms for over 7 years. Her symptoms were often misattributed to behaviours secondary to restrictive anorexia nervosa and borderline personality disorder. Even after appropriate diagnosis and management, she suffered a complicated post-operative course. Patients with psychiatric comorbidities are at higher risk of distress, communication difficulties and inadequate social support, all of which could be better managed with increased multidisciplinary collaboration between endocrine, surgery, psychiatry, pain management and social work. This study highlights the importance of well-rounded patient care that addresses all facets of patient health. This approach not only improves quality of care, but also reduces overall readmissions, revisions, morbidity and mortality.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

The interplay of supports and barriers during the transition to adulthood for youth on the autism spectrum.

PURPOSE: Transition to adulthood is a complex process that involves important life domains such as education, work, independent living, community, health, and social relationships. Autistic youth face the transition with greater challenges than their peers, and there continues to have significant gaps in the services as they approach young adulthood. The study was conducted to understand the complex interplay between supports and barriers to participation in the transition process. METHOD: Data was collected through six focus groups with 24 participants (7 parents, 11 practitioners, 6 autistic youth), digitally audio-recorded, transcribed, and analyzed using thematic analysis. RESULTS: Four themes were reported: Inadequacy of Services, Ambivalence about Formal Services and Support, Understanding Good Partnership, and Evolving Parental Involvement. While parents and practitioners see the fragmented services and lack of comprehensive support as the most prominent challenge, autistic youth feel ambivalent about the type of services they need. Practitioners address the importance of establishing an appropriate level of engagement with parents in the transition process. Autistic youth expect their parents to set a boundary that affirms their independence. CONCLUSIONS: Our study highlights the need to elicit input across different stakeholders to make transition services centralized, easily accessible, and individualized.Implications for RehabilitationIt is important to have a systematic road map, early preparation of families and autistic youth about the array of adult transition services, and a centralized hub of information to be disseminated.Disability service agencies should develop and implement plans for enhancing outreach and services to transition youth on the autism spectrum and their families.Practitioners need to identify locally available resources and channels for outreach and make available service more visible by producing transition-related materials with examples of current legislative information, problem solving, and best practices.Practitioners should consider how autistic youth identify their needs and wants may be different than how service providers and parents conceptualize them.It is critical to capitalize appropriate levels of caregivers/family support and engagement by provision of education about policies and guidelines for communication and collaboration.

Reconstituting and Characterizing Actin-Microtubule Composites with Tunable Motor-Driven Dynamics and Mechanics.

The composite cytoskeleton, comprising interacting networks of semiflexible actin filaments and rigid microtubules, restructures and generates forces using motor proteins such as myosin II and kinesin to drive key processes such as migration, cytokinesis, adhesion, and mechanosensing. While actin-microtubule interactions are key to the cytoskeleton's versatility and adaptability, an understanding of their interplay with myosin and kinesin activity is still nascent. This work describes how to engineer tunable three-dimensional composite networks of co-entangled actin filaments and microtubules that undergo active restructuring and ballistic motion, driven by myosin II and kinesin motors, and are tuned by the relative concentrations of actin, microtubules, motor proteins, and passive crosslinkers. Protocols for fluorescence labeling of the microtubules and actin filaments to most effectively visualize composite restructuring and motion using multi-spectral confocal imaging are also detailed. Finally, the results of data analysis methods that can be used to quantitatively characterize non-equilibrium structure, dynamics, and mechanics are presented. Recreating and investigating this tunable biomimetic platform provides valuable insight into how coupled motor activity, composite mechanics, and filament dynamics can lead to myriad cellular processes from mitosis to polarization to mechano-sensation.

Quantifying Cytoskeleton Dynamics Using Differential Dynamic Microscopy.

Cells can crawl, self-heal, and tune their stiffness due to their remarkably dynamic cytoskeleton. As such, reconstituting networks of cytoskeletal biopolymers may lead to a host of active and adaptable materials. However, engineering such materials with precisely tuned properties requires measuring how the dynamics depend on the network composition and synthesis methods. Quantifying such dynamics is challenged by variations across the time, space, and formulation space of composite networks. The protocol here describes how the Fourier analysis technique, differential dynamic microscopy (DDM), can quantify the dynamics of biopolymer networks and is particularly well suited for studies of cytoskeleton networks. DDM works on time sequences of images acquired using a range of microscopy modalities, including laser-scanning confocal, widefield fluorescence, and brightfield imaging. From such image sequences, one can extract characteristic decorrelation times of density fluctuations across a span of wave vectors. A user-friendly, open-source Python package to perform DDM analysis is also developed. With this package, one can measure the dynamics of labeled cytoskeleton components or of embedded tracer particles, as demonstrated here with data of intermediate filament (vimentin) networks and active actin-microtubule networks. Users with no prior programming or image processing experience will be able to perform DDM using this software package and associated documentation.

Oral histone deacetylase inhibitor HBI-8000 (tucidinostat) in Japanese patients with relapsed or refractory non-Hodgkin's lymphoma: phase I safety and efficacy.

OBJECTIVE: HBI-8000 (tucidinostat) is a novel, oral histone deacetylase inhibitor that selectivity inhibits Class I (histone deacetylase 1, 2, 3) and Class II (histone deacetylase 10) with direct anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It has been approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma. METHODS: This multicenter, prospective phase I dose-escalation trial evaluating the safety of twice weekly HBI-8000 was conducted in Japan. Eligible patients had non-Hodgkin's lymphoma and no available standard therapy. The primary endpoint was maximum tolerated dose; secondary endpoints included anti-tumor activity, safety and pharmacokinetics. RESULTS: Fourteen patients were enrolled in the study. Twelve patients were assessed for dose-limiting toxicity: six patients in the 30 mg BIW cohort had no dose-limiting toxicitys; two of six patients in the 40 mg BIW cohort had asymptomatic dose-limiting toxicitys. Treatment was well tolerated; adverse events were predominantly mild to moderate hematologic toxicities and were managed with dose modification and supportive care. Thirteen patients were included in the efficacy analysis. Objective response was seen in five of seven patients in the 40 mg BIW cohort; three partial responders had adult T-cell leukemia-lymphoma. In the 30 mg BIW cohort, three of six patients had stable disease after the first cycle. CONCLUSIONS: Treatment with HBI-8000 30 and 40 mg BIW were well-tolerated and safe, with hematological toxicities as expected from other studies of histone deacetylase inhibitor. The maximum tolerated dose and recommended dosage for phase II studies of HBI-8000 is 40 mg BIW. Preliminary efficacy results are encouraging.

Parent Attitudes regarding Orthodontists' Role as Potential Administrators of Human Papilloma Virus (HPV) Vaccines.

Objective: To assess parent attitudes regarding orthodontists' role as potential administrators of human papilloma virus (HPV) vaccines. Materials and Methods: 275 parents of adolescents, aged 11-17, who attended the orthodontic clinic at an American university for orthodontic adjustment visits and met inclusion criteria were given information about HPV and HPV vaccines. A paper questionnaire was administered to assess comfort level with orthodontists as HPV vaccinators. Demographic and other potential explanatory characteristics were collected. Descriptive, bivariate, and multivariate ordinal logistic regression analyses were performed with SPSS statistical software v25. Results: The majority of participants were between 31 and 40 years old, with 79.6% identifying as female. 54.3% of the subjects' children identified as female. Although 71.3% of participants identified as Hispanic, 55.3% of the total participants chose to respond to the questionnaire in Spanish. 66.7% of the participants reported education level as high school degree or less. Overall, 52.4% of parents responded that they would be comfortable with orthodontists administering HPV vaccines to their children. Bivariate analysis suggested a significant association (p < 0.05) of parents taking the survey in Spanish and parents' educational attainment with HPV vaccine administration comfort level. Multivariate ordinal logistic regression indicates that parents taking survey in Spanish (adjusted OR: 2.42, 95% CI: 1.24-4.72; p < .01) and parents of male children (adjusted OR: 1.66, 95% CI: 1.01-2.73; p < 047) were comfortable with orthodontists administering the HPV vaccine. Conclusions: The language of the survey influenced parents' comfort level with orthodontists as HPV vaccinators, with Spanish having a positive correlation to comfort level. Parents of male children were more comfortable with orthodontists as HPV vaccinator.

Case series on aripiprazole and dopamine supersensitivity psychosis.

A potential link between switching to aripiprazole and worsening of psychosis was first reported in the early 2000s. There have since been numerous published case reports describing this phenomenon, but only recently has the concept of a theoretical aripiprazole-induced dopamine supersensitivity psychosis (DSP) caused by D2 receptor activation in patients undergoing a switch to aripiprazole appeared in the literature. There is less awareness in clinical practice of the possibility of inducing DSP with aripiprazole, which may be particularly severe in some patients. The objective of this article is to present four cases demonstrating rapid and dramatic onset of DSP during switching to aripiprazole. In each case, a patient with a Diagnostic and statistical manual of mental disorders (5th ed.) diagnosis of schizophrenia experienced severe worsening of psychosis within 4-5 days of abrupt switching to aripiprazole from a full D2 antagonist. To our knowledge, this is the first case series characterizing the previously well-documented worsening of psychosis during switching to aripiprazole specifically as aripiprazole-induced DSP. We discuss clinical relevance, prevention and future directions. Careful cross-titration per clinical practice guidelines may reduce occurrence of DSP during aripiprazole switching or augmentation treatment.

The Role of Acceptance in the Transition to Adulthood: A Multi-Informant Comparison of Practitioners, Families, and Youth with Autism.

This study investigated the role of acceptance during the transition process among autistic young adults, parents, and practitioners. Six focus groups were run and thematic analysis was used to identify four themes: Youth on the autism spectrum discussed transition as a time where Self-Advocacy and Self-Acceptance were salient. Both youth and parents discussed the Lack of Understanding and Acceptance they experience. Particularly, youth highlighted the lack of understanding of sensory needs and parents underscored the lack of understanding by medical professionals. In contrast, practitioners highlighted the presence of Community Openness. Both practitioners and parents discussed Finding Personal Support through Acceptance. Self-acceptance and acceptance of autism are imperative for autistic young adults and families to achieve well-being.

14-3-3 proteins promote synaptic localization of N-methyl d-aspartate receptors (NMDARs) in mouse hippocampal and cortical neurons.

One of the core pathogenic mechanisms for schizophrenia is believed to be dysfunction in glutamatergic synaptic transmissions, particularly hypofunction of N-methyl d-aspartate receptors (NMDARs). Previously we showed that 14-3-3 functional knockout mice exhibit schizophrenia-associated behaviors accompanied by reduced synaptic NMDARs in forebrain excitatory neurons. To investigate how 14-3-3 proteins regulate synaptic localization of NMDARs, here we examined changes in levels of synaptic NMDARs upon 14-3-3 inhibition in primary neurons. Expression of 14-3-3 protein inhibitor (difopein) in primary glutamatergic cortical and hippocampal neurons resulted in lower number of synaptic puncta containing NMDARs, including the GluN1, GluN2A, or GluN2B subunits. In heterologous cells, 14-3-3 proteins enhanced surface expression of these NMDAR subunits. Furthermore, we identified that 14-3-3ζ and ε isoforms interact with NMDARs via binding to GluN2A and GluN2B subunits. Taken together, our results demonstrate that 14-3-3 proteins play a critical role in NMDAR synaptic trafficking by promoting surface delivery of NMDAR subunits GluN1, GluN2A, and GluN2B. As NMDAR hypofunctionality is known to act as a convergence point for progression of symptoms of schizophrenia, further studies on these signaling pathways may help understand how dysfunction of 14-3-3 proteins can cause NMDAR hypofunctionality and lead to schizophrenia-associated behaviors.

Active cytoskeletal composites display emergent tunable contractility and restructuring.

The cytoskeleton is a model active matter system that controls processes as diverse as cell motility and mechanosensing. While both active actomyosin dynamics and actin-microtubule interactions are key to the cytoskeleton's versatility and adaptability, an understanding of their interplay is lacking. Here, we couple microscale experiments with mechanistic modeling to elucidate how connectivity, rigidity, and force-generation affect emergent material properties in composite networks of actin, tubulin, and myosin. We use multi-spectral imaging, time-resolved differential dynamic microscopy and spatial image autocorrelation to show that ballistic contraction occurs in composites with sufficient flexibility and motor density, but that a critical fraction of microtubules is necessary to sustain controlled dynamics. The active double-network models we develop, which recapitulate our experimental findings, reveal that while percolated actomyosin networks are essential for contraction, only composites with comparable actin and microtubule densities can simultaneously resist mechanical stresses while supporting substantial restructuring. The comprehensive phase map we present not only provides important insight into the different routes the cytoskeleton can use to alter its dynamics and structure, but also serves as a much-needed blueprint for designing cytoskeleton-inspired materials that couple tunability with resilience and adaptability for diverse applications ranging from wound healing to soft robotics.

A changing history: When is it a red flag for child abuse?

BACKGROUND AND OBJECTIVE: While a changing history is frequently cited as a red flag for child abuse, no data support which changes are significant, nor the degree to which concern should be increased. We sought to measure the impact of changing caregiver histories on expert assessments of abuse likelihood. METHODS: We used a vignette survey to measure the impact of a changing history on child abuse expert assessments of abuse likelihood and willingness to undertake testing and protective interventions. By randomly varying the presence and magnitude of history changes, we determined their impact on perceived abuse likelihood. RESULTS: Of 494 invited participants, 267 (54 %) completed the survey. The presence of historical changes significantly affected experts' level of concern for abuse and willingness to test or report abuse, though to variable degrees. For example, while a minor change in the timing of an injury did not significantly increase willingness to perform a skeletal survey (OR: 1.5, 95 % CI: 0.8-2.9), a major change in the timing of an injury did (OR: 2.0, 95 % CI: 1.1-3.6). In addition, a change from having no initial history of trauma to then giving a history of accidental trauma significantly lowered the mean estimate of abuse likelihood and triggered significantly less reports to child protective services (OR: 0.02, 95 % CI: 0.003-0.2). CONCLUSION: For abuse experts, some history changes are more concerning than others, with major changes in history, and an initial denial of trauma having the largest impact. Future research regarding changing histories should consider details of the change, rather than treating all changes equally.

Myosin-driven actin-microtubule networks exhibit self-organized contractile dynamics.

The cytoskeleton is a dynamic network of proteins, including actin, microtubules, and their associated motor proteins, that enables essential cellular processes such as motility, division, and growth. While actomyosin networks are extensively studied, how interactions between actin and microtubules, ubiquitous in the cytoskeleton, influence actomyosin activity remains an open question. Here, we create a network of co-entangled actin and microtubules driven by myosin II. We combine dynamic differential microscopy, particle image velocimetry, and particle tracking to show that both actin and microtubules undergo ballistic contraction with unexpectedly indistinguishable characteristics. This contractility is distinct from faster disordered motion and rupturing that active actin networks exhibit. Our results suggest that microtubules enable self-organized myosin-driven contraction by providing flexural rigidity and enhanced connectivity to actin networks. Beyond the immediate relevance to cytoskeletal dynamics, our results shed light on the design of active materials that can be precisely tuned by the network composition.

Efficacy of Low-Dose Epinephrine Continuous Infusion in Neonatal Intensive Care Unit Patients.

OBJECTIVES: Although epinephrine is used in the neonatal intensive care unit, few data exist on efficacy of doses <0.05 mcg/kg/min. This study evaluates the efficacy and safety of low-dose epinephrine continuous infusion at doses <0.05 mcg/kg/min in infants. METHODS: Single-center, retrospective review of hypotensive infants from 2011-2018. Charts were reviewed for initial and maximum epinephrine doses, additional vasoactive agents, short-term efficacy, and adverse effects. The primary outcome was percentage of patients initiated on low-dose epinephrine whose dose did not require titration to ≥0.05 mcg/kg/min. RESULTS: A total of 115 patients met study criteria with 131 distinct occurrences of low-dose epinephrine initiation. Most patients were unresponsive to other vasopressors at the time of epinephrine initiation. The median (IQR) starting dose of low-dose epinephrine was 0.01 (0.01-0.04) mcg/kg/min and median (IQR) maximum dose was 0.04 (0.02-0.08) mcg/kg/min. Fifty-five percent were responders. Patients in this cohort demonstrated significant improvement of blood pressure and urine output (p < 0.001) without adverse effects. CONCLUSIONS: Low-dose epinephrine infusion may be considered as an alternative treatment to standard starting doses in hypotensive neonatal intensive care unit patients.