Brain metastases in clinical trial participants with KRAS-mutated advanced non-small cell lung cancer receiving docetaxel: Pooled data analysis.

OBJECTIVES: Limited data are available on central nervous system (CNS) efficacy with standard-of-care therapies for KRAS-mutated (KRASmut) advanced non-small cell lung cancer (NSCLC). The objective of this study was to investigate the incidence and progression of brain metastases in KRASmut advanced NSCLC treated with docetaxel using pooled data from historical clinical trials. MATERIALS AND METHODS: Data from phase 2/3 trials of docetaxel-containing regimens in advanced NSCLC were sourced from the Medidata platform. Analysis was restricted to stage IIIB-IV KRASmut NSCLC with disease progression after ≥ 1 systemic anticancer therapy. Participants with asymptomatic, treated, and stable brain metastases were included. Endpoints included 12-month CNS disease control rate (CNS-DCR) and CNS progression per Response Evaluation Criteria in Solid Tumors; progression-free survival (PFS); and overall survival (OS). Data were pooled and analyses stratified by baseline brain metastases status. RESULTS: A total of 595 participants were included in the analysis (62 [10%] with baseline brain metastases and 533 [90 %] without). Among participants with brain metastases, 17 (27.4 %) had CNS progression during docetaxel treatment and 12-month CNS-DCR was 75.8 %; 45 (8.4 %) participants without baseline brain metastases developed brain metastases during treatment. In an analysis restricted to patients with metastatic disease, outcomes with and without baseline brain metastases included: median PFS, 3.3 and 4.9 months (p < 0.005); 12-month PFS, 5 % and 16 %; median OS, 6.9 and 10.4 months (p < 0.005); and 12-month OS, 20 % and 44 %, respectively. CONCLUSION: These findings establish CNS progression rates with docetaxel in previously treated KRASmut advanced NSCLC and facilitate interpretation of data from ongoing randomized clinical trials of novel KRAS-targeted therapeutic strategies vs. docetaxel.

Conformation Controlled Hydrogelation of Minimalistic α, γ Hybrid Peptide.

A majority of short peptide (≤7 amino acids) hydrogels are primarily assembled via cross ß-structure formation. In contrast to the natural trend, herein, we report the formation of supramolecular hydrogel from the ultrashort hybrid folded peptide composed of canonical α-amino acid and noncanonical γ-amino acid, Fmoc-γPhe-Phe-OH. The designed hybrid peptide hydrogel is composed of entangled fibers, has viscoelastic properties, exhibits proteolytic stability, and exhibits cytocompatibility with L929 fibroblast cells. Mutating the peptide sequence by altering the position of γPhe from the N-termini to C-termini transforms the self-assembly into crystalline aggregates. Combining FTIR, 2D NMR, and DFT calculations revealed that the hydrogel-forming peptide adopts a C9 H-bonded conformation, resembling the well-known γ-turn. However, the isomeric hybrid peptide adopts an extended structure. The present study highlights the importance of secondary structure in the higher order assembly of minimalist hybrid peptides and broadens the range of secondary structures to design short peptide-based hydrogels.

High-throughput quantitative assessments of the chemical complementarity of celiac disease related IGH CDR3s and a gliadin epitope.

The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of IGH CDR3-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.

Peptide hydrogen-bonded organic frameworks.

Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity. Flexible, ultra-short peptide-based P-HPFs (composed of 3 or fewer amino acids) exhibit adaptable porous topologies that can accommodate a variety of guest molecules and capture hazardous greenhouse gases. Longer, folded peptides present challenges and opportunities in designing P-HPFs. This review highlights recent developments in P-HPFs using ultra-short peptides, folded peptides, and foldamers, showcasing their utility for gas storage, chiral recognition, chiral separation, and medical applications. It also addresses design challenges and future directions in the field.

The Next Horizon of Drug Development: External Control Arms and Innovative Tools to Enrich Clinical Trial Data.

Conducting clinical trials (CTs) has become increasingly costly and complex in terms of designing and operationalizing. These challenges exist in running CTs on novel therapies, particularly in oncology and rare diseases, where CTs increasingly target narrower patient groups. In this study, we describe external control arms (ECA) and other relevant tools, such as virtualization and decentralized clinical trials (DCTs), and the ability to follow the clinical trial subjects in the real world using tokenization. ECAs are typically constructed by identifying appropriate external sources of data, then by cleaning and standardizing it to create an analysis-ready data file, and finally, by matching subjects in the external data with the subjects in the CT of interest. In addition, ECA tools also include subject-level meta-analysis and simulated subjects' data for analyses. By implementing the recent advances in digital health technologies and devices, virtualization, and DCTs, realigning of CTs from site-centric designs to virtual, decentralized, and patient-centric designs can be done, which reduces the patient burden to participate in the CTs and encourages diversity. Tokenization technology allows linking the CT data with real-world data (RWD), creating more comprehensive and longitudinal outcome measures. These tools provide robust ways to enrich the CT data for informed decision-making, reduce the burden on subjects and costs of trial operations, and augment the insights gained for the CT data.

Metal-driven folding and assembly of a minimal ß-sheet into a 3D-porous honeycomb framework.

In contrast to short helical peptides, constrained peptides, and foldamers, the design and fabrication of crystalline 3D frameworks from the ß-sheet peptides are rare because of their high self-aggregation propensity to form 1D architectures. Herein, we demonstrate the formation of a 3D porous honeycomb framework through the silver coordination of a minimal ß-sheet forming a peptide having terminal metal coordinated 4- and 3-pyridyl ligands.

Navigating Uncharted Waters: Comparative Analysis of Clinical Progression and Outcomes in Vestibular Schwannoma Patients with Papilledema and without Hydrocephalus, Versus Those without Papilledema and Hydrocephalus: A Comprehensive Institutional Insight.

BACKGROUND: Papilledema's association with hydrocephalus (HCP)-linked larger vestibular schwannoma (VS) is established but cases lacking concurrent HCP require further investigation. METHODS: This retrospective comparative observational study, conducted from July 2018 to July 2023, examined 120 VS patients undergoing surgery. Patients were categorized into Group 1 (papilledema without HCP) and Group 2 (no papilledema or HCP), with comprehensive data analyzed. RESULTS: In this study, Group 1 (14 patients with papilledema) and Group 2 (106 patients without papilledema or HCP) were compared. Group 1 was younger (mean age 27.21 ± 11.73 years) than Group 2 (mean age 54.66 ± 11.44 years). Both groups had similar symptom durations and tumor detection times. Group 1 had increased vascularity (P = 0.001), elevated cisterna magna protein levels (P = 0.001), and a higher incidence of neurofibromatosis 2 (P = 0.003). They also experienced longer surgeries (P = 0.001) and more blood loss (P = 0.001), leading to extended postoperative complications. Group 2 showed improved postsurgery visual outcomes (P = 0.001), better Glasgow Outcome Scores (P = 0.001), enhanced facial nerve preservation (P = 0.002), and improved hearing on follow-up (P = 0.003). Logistic regression analysis highlighted prolonged surgery duration (P = 0.057) and papilledema (P = 0.0001) as significant factors influencing visual improvement. CONCLUSIONS: Patients with VS require preoperative fundoscopy evaluation due to potential visual loss and papilledema, even without HCP. Early treatment initiation enhances visual and hearing outcomes. Meticulous surgery is vital given the lesion's hypervascular nature and adherence to surrounding structures. Preoperative embolization may aid in preserving neurovascular structures. In developing countries with higher blindness rates, judicious noncontrast computed tomography brain evaluation is crucial for timely detection and treatment initiation of lesions like VS.

Unsupervised Domain Adaptation Using Fourier Phase Enhanced Training Images for Liver Tumors Detection in Multi-phase CT Images.

Computer-aided diagnostic methods, such as automatic and precise liver tumor detection, have a significant impact on healthcare. In recent years, deep learning-based liver tumor detection methods in multi-phase computed tomography (CT) images have achieved noticeable performance. Deep learning frameworks require a substantial amount of annotated training data but obtaining enough training data with high quality annotations is a major issue in medical imaging. Additionally, deep learning frameworks experience domain shift problems when they are trained using one dataset (source domain) and applied to new test data (target domain). To address the lack of training data and domain shift issues in multiphase CT images, here, we present an adversarial learning-based strategy to mitigate the domain gap across different phases of multiphase CT scans. We introduce to use Fourier phase component of CT images in order to improve the semantic information and more reliably identify the tumor tissues. Our approach eliminates the requirement for distinct annotations for each phase of CT scans. The experiment results show that our proposed method performs noticeably better than conventional training and other methods.

Non-COVID-19 Cutaneous Mucormycosis from a Plastic Surgical Perspective.

Background Cutaneous mucormycosis is a rare and fulminant infection associated with high mortality. Plastic surgeons come across this infection in the settings of road traffic accidents, surgical site infections, and as a secondary infection with underlying bacterial soft tissue infections. Due to this infection's rarity and aggressive course, it is essential to initiate prompt multidisciplinary management at the first presentation. With this study, we aim to present a protocol for managing the condition. Methods This is a retrospective observational study of patients with cutaneous mucormycosis managed at a tertiary care hospital from January 1, 2016 to November 30, 2022 excluding patients with mucormycosis who tested positive for coronavirus disease 2019. Results Of 24 patients, 22 were males, and most were in the age group of 41 to 60 years. Sixteen patients survived and five out of eight deceased had comorbidities, six presented primarily without prior debridement, and six had trunk involvement. Conclusion A high index of clinical suspicion is necessary for early diagnosis and management of patients with invasive cutaneous mucormycosis. A multidisciplinary approach with appropriate medical and surgical management can improve outcomes in cases that otherwise carry a high mortality rate.

A Boundary-Enhanced Liver Segmentation Network for Multi-Phase CT Images with Unsupervised Domain Adaptation.

Multi-phase computed tomography (CT) images have gained significant popularity in the diagnosis of hepatic disease. There are several challenges in the liver segmentation of multi-phase CT images. (1) Annotation: due to the distinct contrast enhancements observed in different phases (i.e., each phase is considered a different domain), annotating all phase images in multi-phase CT images for liver or tumor segmentation is a task that consumes substantial time and labor resources. (2) Poor contrast: some phase images may have poor contrast, making it difficult to distinguish the liver boundary. In this paper, we propose a boundary-enhanced liver segmentation network for multi-phase CT images with unsupervised domain adaptation. The first contribution is that we propose DD-UDA, a dual discriminator-based unsupervised domain adaptation, for liver segmentation on multi-phase images without multi-phase annotations, effectively tackling the annotation problem. To improve accuracy by reducing distribution differences between the source and target domains, we perform domain adaptation at two levels by employing two discriminators, one at the feature level and the other at the output level. The second contribution is that we introduce an additional boundary-enhanced decoder to the encoder-decoder backbone segmentation network to effectively recognize the boundary region, thereby addressing the problem of poor contrast. In our study, we employ the public LiTS dataset as the source domain and our private MPCT-FLLs dataset as the target domain. The experimental findings validate the efficacy of our proposed methods, producing substantially improved results when tested on each phase of the multi-phase CT image even without the multi-phase annotations. As evaluated on the MPCT-FLLs dataset, the existing baseline (UDA) method achieved IoU scores of 0.785, 0.796, and 0.772 for the PV, ART, and NC phases, respectively, while our proposed approach exhibited superior performance, surpassing both the baseline and other state-of-the-art methods. Notably, our method achieved remarkable IoU scores of 0.823, 0.811, and 0.800 for the PV, ART, and NC phases, respectively, emphasizing its effectiveness in achieving accurate image segmentation.

Management dilemma in a rare case of pituitary apoplexy with akinetic mutism in the setting of ruptured junctional brain aneurysm: A case report and literature review.

Backgound: Pituitary apoplexy is associated with stroke, head injury, and brain tumors. Still, its presentation due to the ruptured aneurysm is rare and its presentation with akinetic mutism has not been reported. Case Description: The patient in the present study is 21-year-old female who presented in our emergency department in an altered sensorium with Glasgow comma score (GCS) E2V1M1. She was intubated and resuscitated. Routine blood investigations, lipid profile, and hormonal studies were normal. Initial noncontrast computed tomography (NCCT) head revealed subarachnoid hemorrhage in the interhemispheric fissure and evidence of bleeding in the pituitary gland. Magnetic resonance imaging (MRI) brain was soon done, which showed an infarct and hemorrhage in the pituitary gland; there was an evidence of an infarct in the bilateral medial frontal gyrus, basal ganglia, and supplementary motor area. MR arteriography revealed an aneurysm at the left A1-anterior communicating artery (Acom) junction directed superomedially with diffuse spasm in a bilateral anterior cerebral artery. Pterional craniotomy was done with clipping of the aneurysm and evacuation of blood clots from the interhemispheric fissure and pituitary gland. Histopathology features suggestive of the non-functioning pituitary tumor with interspersed hemorrhagic necrosis. Intraarterial vasodilation with microcatheter injection was given, but vasospasm did not improve. Postoperatively, Levodopa was started. She used to track objects in front of her eye and started nodding her head in "yes and no fashion," with power in limbs improved to 3/5 at 6 months of follow-up. Conclusion: Pituitary apoplexy with ruptured A1-Acom junction aneurysm with nonfunctioning pituitary macroadenoma is rare, and its presentation with akinetic mutism has not been reported. As there is scarce literature suggesting an association between pituitary apoplexy and ruptured aneurysm, it is challenging to comment regarding its pathogenesis. Although akinetic mutism generally has a poor prognosis, it may respond to Levodopa with a better outcome.

Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption.

Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 µg/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.

Anticryptococcal activity and mechanistic studies of short amphipathic peptides.

Cryptococcus neoformans, an opportunistic fungal pathogen, causes cryptococcosis in immunocompromised persons. A series of modified L-histidines-containing peptides are synthesized that exhibit promising activity against C. neoformans. Analog 11d [L-His(2-adamantyl)-L-Trp-L-His(2-phenyl)-OMe] produced potency with an IC50 of 3.02 µg/ml (MIC = 5.49 µg/ml). This peptide is noncytotoxic and nonhaemolytic at the MIC and displays synergistic effects with amphotericin B at subinhibitory concentration. Mechanistic investigation of 11d using microscopic tools indicates cell wall and membrane disruption of C. neoformans, while flow cytometric analysis confirms cell death by apoptosis. This study indicates that 11d exhibits antifungal potential and acts via the rapid onset of action.

Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Polyamine metabolizing rhizobacteria Pseudomonas sp. GBPI_506 modulates hormone signaling to enhance lateral roots and nicotine biosynthesis in Nicotiana benthamiana.

Beneficial rhizobacteria in the soil are important drivers of plant health and growth. In this study, we provide the draft genome of a root colonizing and auxin-producing Pseudomonas sp. strain GBPI_506. The bacterium was investigated for its contribution in the growth of Nicotiana benthamiana (Nb) and biosynthesis of nicotine. The bacterium showed chemotaxis towards root exudates potentially mediated by putrescine, a polyamine compound, to colonize the roots of Nb. Application of the bacterium with the roots of Nb, increased plant biomass and total soluble sugars in the leaves, and promoted lateral root (LR) development as compared to the un-inoculated plants. Confocal analysis using transgenic (DR5:GFP) Arabidopsis showed increased auxin trafficking in the LR of inoculated plants. Upregulation of nicotine biosynthesis genes and genes involved in salicylic acid (SA) and jasmonic acid (JA) signaling in the roots of inoculated plants suggested increased nicotine biosynthesis as a result of bacterial application. An increased JA content in roots and nicotine accumulation in leaves provided evidence on JA-mediated upregulation of nicotine biosynthesis in the bacterized plants. The findings suggested that the bacterial root colonization triggered networking between auxin, SA, and JA to facilitate LR development leading to enhanced plant growth and nicotine biosynthesis in Nb.

Peptide-based drug discovery: Current status and recent advances.

The progressive development of peptides from reaction vessels to life-saving drugs via rigorous preclinical and clinical assessments is fascinating. Peptide therapeutics have gained momentum with the evolution of techniques in peptide chemistry, such as microwave irradiation in solid- and solution-phase synthesis, ligation chemistry, recombinant synthesis, and amalgamation with synthetic tools, including metal catalysis. Diverse emerging technologies, such as DNA-encoded libraries (DELs) and display techniques, are changing the status quo in the discovery of peptide therapeutics. In this review, we analyzed US Food and Drug Administration (FDA)-approved peptide drugs and those in clinical trials, highlighting recent advances in peptide-based drug discovery.

Synthetic amino acids-derived peptides target Cryptococcus neoformans by inducing cell membrane disruption.

We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 µg/mL; MIC = 3.46 µg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 µg/mL; MIC = 2.46 µg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 µg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.

Exploring Helical Peptides and Foldamers for the Design of Metal Helix Frameworks: Current Trends and Future Perspectives.

Flexible and biocompatible metal peptide frameworks (MPFs) derived from short and ultra-short peptides have been explored for the storage of greenhouse gases, molecular recognition, and chiral transformations. In addition to short flexible peptides, peptides with specifically folded conformations have recently been utilized to fabricate a variety of metal helix frameworks (MHFs). The secondary structures of the peptides govern the structure-assembly relationship and thereby control the formation of three-dimensional (3D)-MHFs. Particularly, the hierarchical structural organization of peptide-based MHFs has not yet been discussed in detail. Here, we describe the recent progress of metal-driven folded peptide assembly to construct 3D porous structures for use in future energy storage, chiral recognition, and biomedical applications, which could be envisioned as an alternative to the conventional metal-organic frameworks (MOFs).

A Novel Technique for the Correction of Unilateral Craniofacial Fibrous Dysplasia Using Multiplanar Sequential Cutting Guides.

In this unique case report, the authors have described a new method for the correction of unilateral craniofacial fibrous dysplasia by using sequential cutting guides. Due to the complex 3-dimensional anatomy of zygoma, it needs to be chiseled in multiple planes to mimic the normal contralateral side. To achieve this, 3 different guides were used one after the other to perform osteotomies in different planes and remove the excess fibrous bone.

Cannabis and the heart: unchartered territory.

Cannabis is one of the most commonly used illicit drugs. It is a psychoactive drug with tetrahydrocannabinol being the main active ingredient. With increasing decriminalization and legalization of marijuana use in the USA, it is essential to study its long-term effects on cardiovascular diseases, a leading cause of death in the USA. Cannabis can trigger acute myocardial infarction in otherwise healthy young individuals, affect atherogenesis, arrhythmia, develop Takotsubo cardiomyopathy and cannabis arteritis. The only definitive treatment for these pathologies is complete abstinence. In this review we focus on discussing the long-term effects of tetrahydrocannabinol on cardiovascular pathologies, its pathophysiology and a brief discussion on its clinical features and definitive management.

Cannabis is one of the most commonly abused drugs. It is a stimulant with tetrahydrocannabinol being the main active ingredient. With increasing decriminalization and legalization of marijuana use in the USA, it is essential to study its long-term effects on heart diseases, a leading cause of death in the USA. Cannabis can trigger heart attacks in otherwise healthy young individuals, affect normal beating of the heart and heart muscle functions; and also play a role in narrowing of the blood vessels reducing the blood to distant parts of the body. The only definitive treatment for these marijuana induced heart and blood vessel diseases is completely restricting the use of the drug. In this review, we focus on discussing the long-term effects of tetrahydrocannabinol on development of certain heart and blood vessel diseases and briefly discuss its clinical features and definitive treatment options for complete restrain from marijuana.