Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 ...cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor’s genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.
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•Vast genomic and transcriptomic heterogeneity of GBM tumor cells•Characterization of individual GBM infiltrating cells in peritumoral tissue•Possible convergent strategy of infiltration between highly variable tumors•Myeloid cells participate in enhancing tumor growth, survival, and dissemination
Darmanis et al. perform single-cell transcriptomic analyses of neoplastic and stromal cells within and proximal to primary glioblastomas. The authors describe a population of neoplastic-infiltrating glioblastoma cells as well as a putative role of tumor-infiltrating immune cells in supporting tumor growth.
In the 2021 residency application cycle, the average otolaryngology applicant applied to more than half of programs. Increasing application numbers make it difficult for applicants to stand out to ...programs of interest and for programs to identify applicants with sincere interest.
As part of the 2021 Match, otolaryngology applicants could participate in a preference signaling process, signaling up to 5 programs of particular interest at the time of application submission. Programs received a list of applicants who submitted signals to consider during interview offer deliberations. Applicants and program directors completed surveys to evaluate the signaling process and assess the impact of signals on interview offers.
All otolaryngology residency programs participated in the signaling process. In total, 611 students submitted applications for otolaryngology residency programs, 559 applicants submitted a Match list including an otolaryngology program, and 558 applicants participated in the signaling process. The survey response rate was 42% for applicants (n = 233) and 52% for program directors (n = 62). The rate of receiving an interview offer was significantly higher from signaled programs (58%) than from both nonsignaled programs (14%; P < .001) and the comparative nonsignal program (23%; P < .001) (i.e., the program an applicant would have signaled given a sixth signal). This impact was consistent across the spectrum of applicant competitiveness. Applicants (178, 77%) and program directors (53, 91%) strongly favored continuing the program.
Many specialties face high residency application numbers. Programs have difficulty identifying applicants with sincere interest, and applicants face limited opportunities to identify programs of particular interest. Applicants to these specialties may benefit from a preference signaling process like that in otolaryngology. Additional evaluation is needed to determine the impact of signals across racial and demographic lines and to validate these early outcomes.
P‐glycoprotein (P‐gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P‐gp and its homologs have provided insights into its transport cycle, but ...questions remain regarding how P‐gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P‐gp co‐crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP‐hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide‐binding domains. A new ligand‐binding site on the surface of P‐gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P‐gp. These results represent significant advances in the understanding of how P‐gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.
To present the first year-over-year data comparison of preference signaling for residency interviews in the otolaryngology application marketplace.
Cross-sectional study conducted over 2 application ...cycles.
Otolaryngology training programs in the United States.
Otolaryngology residency applicants were invited to participate in preference signaling during the 2021 and 2022 application cycles. Submissions were collected using a web-based interface. The distribution of signals among programs was evaluated descriptively and in relationship to Doximity program reputation rankings. Surveys were sent to applicants to assess general attitudes and the number of interview invitations received from signaled and nonsignaled programs. Surveys were sent to programs to evaluate use of signals and the impact on match results.
Programs received a range of signals, from 0 to 66, with 50% of signals going to 24% of programs in 2022, which was similarly found in 2021. Programs of higher rank tended to receive more signals. Overall, >87% of surveyed applicants received an interview offer from at least 1 program that they signaled. In 2021 and 2022, applicants were 2.6 times more likely to get an interview from a signaled program than a comparator nonsignaled program. A greater positive impact on interview offer rate was seen for less competitive applicants. Signaling was viewed favorably by the majority of surveyed applicants and programs.
Preference signaling for otolaryngology residency interviews demonstrates a promising mechanism to improve applicant visibility to programs during the application cycle. This impact is consistent over 2 application cycles.
To report the outcomes of repeat stereotactic radiosurgery (SRS), deferring whole-brain radiation therapy (WBRT), for distant intracranial recurrences and identify factors associated with prolonged ...overall survival (OS).
We retrospectively identified 652 metastases in 95 patients treated with 2 or more courses of SRS for brain metastases, deferring WBRT. Cox regression analyzed factors predictive for OS.
Patients had a median of 2 metastases (range, 1-14) treated per course, with a median of 2 courses (range, 2-14) of SRS per patient. With a median follow-up after first SRS of 15 months (range, 3-98 months), the median OS from the time of the first and second course of SRS was 18 (95% confidence interval CI 15-24) and 11 months (95% CI 6-17), respectively. On multivariate analysis, histology, graded prognostic assessment score, aggregate tumor volume (but not number of metastases), and performance status correlated with OS. The 1-year cumulative incidence, with death as a competing risk, of local failure was 5% (95% CI 4-8%). Eighteen (24%) of 75 deaths were from neurologic causes. Nineteen patients (20%) eventually received WBRT. Adverse radiation events developed in 2% of SRS sites.
Multiple courses of SRS, deferring WBRT, for distant brain metastases after initial SRS, seem to be a safe and effective approach. The graded prognostic assessment score, updated at each course, and aggregate tumor volume may help select patients in whom the deferral of WBRT might be most beneficial.
Effective bioremediation of hydrocarbons requires innovative approaches to minimize phosphate precipitation in soils of different buffering capacities. Understanding the mechanisms underlying ...sustained stimulation of bacterial activity remains a key challenge for optimizing bioremediationparticularly in northern regions. Positron emission tomography (PET) can trace microbial activity within the naturally occurring soil structure of intact soils. Here, we use PET to test two hypotheses: (1) optimizing phosphate bioavailability in soil will outperform a generic biostimulatory solution in promoting hydrocarbon remediation and (2) oligotrophic biostimulation will be more effective than eutrophic approaches. In so doing, we highlight the key bacterial taxa that underlie aerobic and anaerobic hydrocarbon degradation in subarctic soils. In particular, we showed that (i) optimized phosphate bioavailability outperformed generic biostimulatory solutions in promoting hydrocarbon degradation, (ii) oligotrophic biostimulation is more effective than eutrophic approaches, and (iii) optimized biostimulatory solutions stimulated specific soil regions and bacterial consortia. The knowledge gleaned from this study will be crucial in developing field-scale biodegradation treatments for sustained stimulation of bacterial activity in northern regions.
Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the ...experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP. Calculated structure accuracy improved dramatically in this round, implying that models should now be much more useful for resolving many sorts of experimental difficulties. To test this, selected models for seven unsolved targets were provided to the experimental groups. These models were from the AlphaFold2 group, who overall submitted the most accurate predictions in CASP14. Four targets were solved with the aid of the models, and, additionally, the structure of an already solved target was improved. An a posteriori analysis showed that, in some cases, models from other groups would also be effective. This paper provides accounts of the successful application of models to structure determination, including molecular replacement for X‐ray crystallography, backbone tracing and sequence positioning in a cryo‐electron microscopy structure, and correction of local features. The results suggest that, in future, there will be greatly increased synergy between computational and experimental approaches to structure determination.
Demarcation of malignant brain tumor boundaries is critical to achieve complete resection and to improve patient survival. Contrast-enhanced brain magnetic resonance imaging (MRI) is the gold ...standard for diagnosis and pre-surgical planning, despite limitations of gadolinium (Gd)-based contrast agents to depict tumor margins. Recently, solid metal-based nanoparticles (NPs) have shown potential as diagnostic probes for brain tumors. Gold nanoparticles (GNPs) emerged among those, because of their unique physical and chemical properties and biocompatibility. The aim of the present study is to review the application of GNPs for
and
brain tumor diagnosis.
We performed a PubMed search of reports exploring the application of GNPs in the diagnosis of brain tumors in biological models including cells, animals, primates, and humans. The search words were "gold" AND "NP" AND "brain tumor." Two reviewers performed eligibility assessment independently in an unblinded standardized manner. The following data were extracted from each paper: first author, year of publication, animal/cellular model, GNP geometry, GNP size, GNP coating i.e., polyethylene glycol (PEG) and Gd, blood-brain barrier (BBB) crossing aids, imaging modalities, and therapeutic agents conjugated to the GNPs.
The PubMed search provided 100 items. A total of 16 studies, published between the 2011 and 2017, were included in our review. No studies on humans were found. Thirteen studies were conducted
on rodent models. The most common shape was a nanosphere (12 studies). The size of GNPs ranged between 20 and 120 nm. In eight studies, the GNPs were covered in PEG. The BBB penetration was increased by surface molecules (nine studies) or by means of external energy sources (in two studies). The most commonly used imaging modalities were MRI (four studies), surface-enhanced Raman scattering (three studies), and fluorescent microscopy (three studies). In two studies, the GNPs were conjugated with therapeutic agents.
Experimental studies demonstrated that GNPs might be versatile, persistent, and safe contrast agents for multimodality imaging, thus enhancing the tumor edges pre-, intra-, and post-operatively improving microscopic precision. The diagnostic GNPs might also be used for multiple therapeutic approaches, namely as "theranostic" NPs.
Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating ...condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.
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