Neoadjuvant Immunotherapy Effectiveness in Patients With Microsatellite Instability-High (MSI-H) Gastric Cancer.

Purpose This research work evaluates monotherapy with checkpoint inhibitors (CPI). as a neoadjuvant treatment for patients with Microsatellite Instability-High (MSI-H) locally advanced gastric cancer. Methods Here we present the results of the retrospective study from Napalkov Cancer Center over 4.5 years on patients with MSI-H locally advanced gastric cancer. A total of 566 patients were analyzed, 18 of whom were included in the research, focusing on clinical response rate, surgical pathology, 'watch and wait' strategy, and safety outcomes on an exploratory basis. Patients were assigned to four to eight neoadjuvant cycles of CPI, followed by surgery. Results The objective response to neoadjuvant CPI in patients with MSI-H gastric cancer was 77.8%. Complete response was achieved in five (27.8%) and partial response in nine (50%) patients, accordingly. Surgery was performed on 14 patients. Complete margin-free (R0) resection rates were 100%. Downstaging was observed in 12 out of 14 patients. Histopathologic complete response rates (pathologic complete response or Tumor Regression Grade-major response (TRG1)) were achieved in eight (57.1%) patients. No disease progression was detected with a median follow-up of 33.7 months (4.4-55.7 months). Clinically significant adverse events were not observed. Conclusion CPI in a neoadjuvant setting for patients with MSI-H locally advanced gastric cancer is highly effective and safe.

Quantification of species composition in grass-clover swards using RGB and multispectral UAV imagery and machine learning.

Introduction: Growing grass-legume mixtures for forage production improves both yield productivity and nutritional quality, while also benefiting the environment by promoting species biodiversity and enhancing soil fertility (through nitrogen fixation). Consequently, assessing legume proportions in grass-legume mixed swards is essential for breeding and cultivation. This study introduces an approach for automated classification and mapping of species in mixed grass-clover swards using object-based image analysis (OBIA). Methods: The OBIA procedure was established for both RGB and ten band multispectral (MS) images capturedby an unmanned aerial vehicle (UAV). The workflow integrated structural (canopy heights) and spectral variables (bands, vegetation indices) along with a machine learning algorithm (Random Forest) to perform image segmentation and classification. Spatial k-fold cross-validation was employed to assess accuracy. Results and discussion: Results demonstrated good performance, achieving an overall accuracy of approximately 70%, for both RGB and MS-based imagery, with grass and clover classes yielding similar F1 scores, exceeding 0.7 values. The effectiveness of the OBIA procedure and classification was examined by analyzing correlations between predicted clover fractions and dry matter yield (DMY) proportions. This quantification revealed a positive and strong relationship, with R2 values exceeding 0.8 for RGB and MS-based classification outcomes. This indicates the potential of estimating (relative) clover coverage, which could assist breeders but also farmers in a precision agriculture context.

Diagnostic Algorithm for Intracranial Lesions in the Emergency Department: Effectiveness of the Relative Brain Volume and Hounsfield Unit Value Measured by Perfusion Tomography.

Background Early treatment of intracranial lesions in the emergency department is crucial, but it can be challenging to differentiate between them. This differentiation is essential because the treatment of each type of lesion is different. Cerebral computed tomography perfusion (CTP) imaging can help visualize the vascularity of brain lesions and provide absolute quantification of physiological parameters. Compared to magnetic resonance imaging, CTP has several advantages, such as simplicity, wide availability, and reproducibility. Purpose This study aimed to assess the effectiveness of Hounsfield units (HU) in measuring the density of hypercellular lesions and the ability of CTP to quantify hemodynamics in distinguishing intracranial space-occupying lesions. Methods A retrospective study was conducted from March 2016 to March 2022. All patients underwent CTP and CT scans, and relative cerebral blood volume (rCBV) and HU were obtained for intracranial lesions. Results We included a total of 244 patients in our study. This group consisted of 87 (35.7%) individuals with glioblastomas (GBs), 48 (19.7%) with primary central nervous system lymphoma (PCNSL), 45 (18.4%) with metastases (METs), and 64 (26.2) with abscesses. Our study showed that the HUs for METs were higher than those for GB (S 57.4% and E 88.5%). In addition, rCBV values for PCNSL and abscesses were lower than those for GB and METs. The HU in PCNSL was higher than those in abscesses (S 94.1% and E 96.6%). Conclusion PCT parameters provide valuable information for diagnosing brain lesions. A comprehensive assessment improves accuracy. Combining rCBV and HU enhances diagnostic accuracy, making it a valuable tool for distinguishing between lesions. PCT's widespread availability allows for the use of both anatomical and functional information with high spatial resolution for diagnosing and managing brain tumor patients.

From adsorption to crystallization of proteins: Evidence for interface-assisted nucleation.

Protein crystallization is among the key processes in biomolecular research, but the underlying mechanisms are still elusive. Here, we address the role of inevitable interfaces for the nucleation process. Quartz crystal microbalance with dissipation monitoring (QCM-D) with simultaneously optical microscopy, confocal microscopy, and grazing-incidence small angle X-rays scattering (GISAXS) were employed to investigate the temporal behavior from the initial stage of protein adsorption to crystallization. Here we studied the crystallization of the Human Serum Albumin (HSA), the most abundant blood protein, in the presence of a charged surface and a trivalent salt. We found evidence for interface-assisted nucleation of crystals. The kinetic stages involved are initial adsorption followed by enhanced adsorption after longer times, subsequent nucleation, and finally crystal growth. The results highlight the importance of interfaces for protein phase behavior and in particular for nucleation.

The ß2-adrenergic receptor agonist formoterol attenuates necrosis and apoptosis in the rat myocardium under experimental stress-induced cardiac injury.

BACKGROUND: Currently, there is no effective therapy for takotsubo syndrome (stress-induced cardiac injury in humans) in the clinics. It has previously been shown that ß2-adrenergic receptor (ß2-AR) agonist formoterol reduces cardiomyocyte injury in experimental takotsubo syndrome. OBJECTIVES: The aim of this study was to investigate whether formoterol prevents apoptosis and necrosis of cardiomyocytes and endothelial cells in stress-induced cardiomyopathy. METHODS: Stress-induced cardiac injury was induced by immobilization of rats for 2, 6, and 24 hours. RESULTS: The myocardium of stressed rats showed a reduction in contractility and histological manifestations of cardiomyocyte damage: karyopyknosis, perinuclear edema of cardiomyocytes and endothelial cells, and microcirculation disturbances augmented with extended exposure to stress. In addition, apoptosis of endothelial cells was detected 6 hours after the onset of stress and peaked at 24 hours. Apoptosis of cardiomyocytes significantly gained only after 24 hours of stress exposure. These morphological alterations were associated with increased levels of serum creatine kinase-MB, syndecan-1, and thrombomodulin after 24 hours of stress. Administration of ß2-AR agonist formoterol (50 µg/kg) four times during 24-hour stress exposure led to the improvement in myocardial inotropy, decrease in the severity of histological signatures, reduction in the number of TUNEL-positive cardiomyocytes, serum creatine kinase-MB, syndecan-1, and thrombomodulin levels. CONCLUSION: Present data suggest that apoptosis and necrosis of cardiomyocytes and necrosis of endothelial cells in stress-induced cardiac injury can be mitigated by activation of the ß2-AR. However, formoterol did not eliminate completely cardiomyocyte apoptosis, histological alterations, or endothelium injury markers under stress.

Functional and Structural Cerebellar-Behavior Relationships in Aging.

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.

Sex-steroid hormones relate to cerebellar structure and functional connectivity across adulthood.

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17ß-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17ß-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

Immune checkpoint markers and tumour mutation burden in Wilms tumour: a study of 59 cases.

Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). Thirteen WTs (13/59, 22%) were positive for PD-L1 (8 primary, 5 metastatic; CPS 1.11-3.42). Positive PD-L1 expression was associated with diffuse anaplasia (p<0.05) and significantly shorter progression-free survival (p<0.05) among WTs with favourable histology (n=39). CD8+ lymphocytes were present in all analysed WTs. A subset of CD8+ cells co-expressed PD-1, which was associated with favourable histology and treatment. MMR IHC stains identified two (2/18, 11%) WTs with isolated PMS2 loss. All six WTs analysed for TMB showed low mutation burden. We found CD8+ lymphocytes in all analysed WTs and identified a fraction of WT (17.8% of primary and 35.8% of metastatic) with positive PD-L1 CPS, suggesting potential response to ICIs in some patients.

DPPM-Bridged Binuclear Pt(II) Pincer Complexes: Chemistry, Structure, and Photophysics in Solution Revisited.

A series of luminescent binuclear ([dppm{Pt(NNC)}2]2+) and mononuclear ([PPh3Pt(NNC)]+) complexes containing pincer ligands were synthesized and characterized. Photophysical characteristics of both types of complexes were studied in dichloromethane solution. In the solid phase, the binuclear compounds adopt a syn configuration where the {Pt(NNC)} fragments are held together due to intramolecular Pt-Pt bonding and π-stacking of the pincer ligand aromatic systems. Analysis of the complexes' molecular structure in solution by multinuclear NMR spectroscopy showed that the stacked intramolecular configuration is retained in fluid media, which is in complete agreement with a considerable red shift of the emission wavelength due to formation of the intramolecular Pt-Pt bond, leading to the transformation of an emissive excited state to 3MMLCT. It was also found that triethylamine quenches the emission of both types of complexes; the mechanism of quenching is a combination of dynamic and static channels of excited-state deactivation. In the case of binuclear complexes, deprotonation of the dppm methylene bridge by triethylamine also contributes to the chromophore quenching. To explain the observed chemistry of binuclear complex interactions with Et3N, a chemical equilibrium scheme was suggested, which was confirmed by quantitative monitoring of the 31P signal variations as a function of triethylamine concentration.

Methyl Methacrylate Copolymer with Pendant Thioxanthenone Groups as Active Layer for Resistive Memory Devices.

An electro-active copolymer of methyl methacrylate and 2-((4-acroylpiperazine-1-yl)methyl)-9H-thioxanthene-9-one (poly(MMA-co-ThS)) was synthesized by radical polymerization. The copolymer has good solubility in most organic solvents, thermal stability up to 282 °C and excellent ability to form thin films on silicon wafers. Poly(MMA-co-ThS) films exhibited an electrochemical and electrochromic activity resulting in the formation of long-lived radical anion states of pendant thioxanthone groups inside the film. These states exhibit optical transitions in the visible region as a broad optical absorption band, 500 < l < 900 nm (1.38

The Effect of Photodynamic Therapy on Enterococcus spp. and Its Application in Dentistry: A Scoping Review.

Enterococci spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated infections (HAIs). Many of these infections become serious diseases that are difficult to resolve, specifically when multidrug-resistant (MDR) strains cause them. In recent years, the number of MDR strains of Enterococcus spp. has increased significantly. This increased prevalence of MDR strains produces significant pressure to generate more antimicrobial therapies, but there is a decline in the production of new antibiotics, driving the development of complementary therapies, such as photodynamic therapy (PDT). PDT combines a photosensitizer agent (PS), light, and oxygen to cause photooxidative stress in bacterial cells. PDT can eradicate Enterococcus spp. contaminations, improve the classic cleaning processes, and eradicate the bacteria in dental pieces. PDT's effectiveness can be improved with nanoparticles that function as carriers. Our work aims to describe the advances in PDT against Enterococcus spp. as a complement to antibiotic therapy, focusing on infections by Enterococcus faecium and Enterococcus faecalis, dental hygiene, and using nanoparticles to improve the antimicrobial effect. A systematic bibliographic search without a meta-analysis was conducted on various databases, using inclusion and exclusion criteria to identify the most relevant research. Of the 193 non-redundant articles found, 65 were selected for a systematic review, from which a summary table was created and a manual description was made. Photodynamic therapy for treating E. faecium and E. faecalis is a widely studied area, with promising results concerning bactericidal effectiveness and reductions in biofilm formation, particularly in regard to dental hygiene. Because most of the studies were conducted in vitro or ex vivo, the results indicated that there were not sufficient data to initiate clinical trials for safety and efficacy studies on humans.

Optical Sensing of Tissue Freezing Depth by Sapphire Cryo-Applicator and Steady-State Diffuse Reflectance Analysis.

This work describes a sapphire cryo-applicator with the ability to sense tissue freezing depth during cryosurgery by illumination of tissue and analyzing diffuse optical signals in a steady-state regime. The applicator was manufactured by the crystal growth technique and has several spatially resolved internal channels for accommodating optical fibers. The method of reconstructing freezing depth proposed in this work requires one illumination and two detection channels. The analysis of the detected intensities yields the estimation of the time evolution of the effective attenuation coefficient, which is compared with the theoretically calculated values obtained for a number of combinations of tissue parameters. The experimental test of the proposed applicator and approach for freezing depth reconstruction was performed using gelatin-based tissue phantom and rat liver tissue in vivo. It revealed the ability to estimate depth up to 8 mm. The in vivo study confirmed the feasibility of the applicator to sense the freezing depth of living tissues despite the possible diversity of their optical parameters. The results justify the potential of the described design of a sapphire instrument for cryosurgery.

Crystal Nucleation in Supercooled Atomic Liquids.

The liquid-to-solid phase transition is a complex process that is difficult to investigate experimentally with sufficient spatial and temporal resolution. A key aspect of the transition is the formation of a critical seed of the crystalline phase in a supercooled liquid, that is, a liquid in a metastable state below the melting temperature. This stochastic process is commonly described within the framework of classical nucleation theory, but accurate tests of the theory in atomic and molecular liquids are challenging. Here, we employ femtosecond x-ray diffraction from microscopic liquid jets to study crystal nucleation in supercooled liquids of the rare gases argon and krypton. Our results provide stringent limits to the validity of classical nucleation theory in atomic liquids, and offer the long-sought possibility of testing nonclassical extensions of the theory.

Softmax parameterization of the occupation numbers for natural orbital functionals based on electron pairing approaches.

Within the framework of natural orbital functional theory, having a convenient representation of the occupation numbers and orbitals becomes critical for the computational performance of the calculations. Recognizing this, we propose an innovative parametrization of the occupation numbers that takes advantage of the electron-pairing approach used in Piris natural orbital functionals through the adoption of the softmax function, a pivotal component in modern deep-learning models. Our approach not only ensures adherence to the N-representability of the first-order reduced density matrix (1RDM) but also significantly enhances the computational efficiency of 1RDM functional theory calculations. The effectiveness of this alternative parameterization approach was assessed using the W4-17-MR molecular set, which demonstrated faster and more robust convergence compared to previous implementations.

Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Electrostatic Control of Nonlinear Photonic-Crystal Polaritons in a Monolayer Semiconductor.

Integration of 2D semiconductors with photonic crystal slabs provides an attractive approach to achieving strong light-matter coupling and exciton-polariton formation in a chip-compatible geometry. However, for the development of practical devices, it is crucial that polariton excitations are easily tunable and exhibit a strong nonlinear response. Here we study neutral and charged exciton-polaritons in an electrostatically gated photonic crystal slab with an embedded monolayer semiconductor MoSe2 and experimentally demonstrate a novel approach to optical control based on polariton nonlinearity. We show that spatial modulation of the dielectric environment within the photonic crystal unit cell results in the formation of two distinct excitonic species with significantly different nonlinear responses of the corresponding charged exciton-polaritons under optical pumping. This behavior enables optical switching with ultrashort laser pulses and can be sensitively controlled via an electrostatic gate voltage. Our results open new avenues toward the development of active polaritonic devices in a compact chip-compatible implementation.

Nanoironing van der Waals Heterostructures toward Electrically Controlled Quantum Dots.

Assembling two-dimensional van der Waals (vdW)-layered materials into heterostructures is an exciting development that sparked the discovery of rich correlated electronic phenomena. vdW heterostructures also offer possibilities for designer device applications in areas such as optoelectronics, valley- and spintronics, and quantum technology. However, realizing the full potential of these heterostructures requires interfaces with exceptionally low disorder which is challenging to engineer. Here, we show that thermal scanning probes can be used to create pristine interfaces in vdW heterostructures. Our approach is compatible at both the material- and device levels, and monolayer WS2 transistors show up to an order of magnitude improvement in electrical performance from this technique. We also demonstrate vdW heterostructures with low interface disorder enabling the electrical formation and control of quantum dots that can be tuned from macroscopic current flow to the single-electron tunneling regime.

Left ventricular unloading via percutaneous assist device during extracorporeal membrane oxygenation in acute myocardial infarction and cardiac arrest.

INTRODUCTION: A feared complication of an acute myocardial infarction (AMI) is cardiac arrest (CA). Even if return of spontaneous circulation is achieved, cardiogenic shock (CS) is common. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) supports patients with CS and is often used in conjunction with an Impella device (2.5 and CP) to off-load the left ventricle, although limited evidence supports this approach. METHODS: The goal of this study was to determine whether a mortality difference was observed in VA-ECMO alone versus VA-ECMO with Impella (ECPELLA) in patients with CS from AMI and CA. A retrospective chart review of 50 patients with AMI-CS and CA and were supported with VA-ECMO (n = 34) or ECPELLA (n = 16) was performed. The primary outcome was all-cause mortality at 6-months from VA-ECMO or Impella implantation. Secondary outcomes included in-hospital mortality and complication rates between both cohorts and intensive care unit data. RESULTS: Baseline characteristics were similar, except patients with ST-elevation myocardial infarction were more likely to be in the VA-ECMO group (p = 0.044). The ECPELLA cohort had significantly worse survival after VA-ECMO (SAVE) score (p = 0.032). Six-month all-cause mortality was not significantly different between the cohorts, even when adjusting for SAVE score. Secondary outcomes were notable for an increased rate of minor complications without an increased rate of major complications in the ECPELLA group. CONCLUSIONS: Randomized trials are needed to determine if a mortality difference exists between VA-ECMO and ECPELLA platforms in patients with AMI complicated by CA and CS.

Feline aortic thromboembolism with and without congestive heart failure did not exhibit hypercoagulability using a novel viscoelastic coagulation monitor.

OBJECTIVE: To demonstrate hypercoagulability with a benchtop viscoelastic monitor in cats with congestive heart failure (CHF) and/or aortic thromboembolism (ATE) compared to controls. METHODS: 97 cats were enrolled throughout this prospective observational cohort study from September 2022 through October 2023. Cats were grouped by diagnosis of CHF, ATE, ATE plus CHF, or controls. Enrollment required diagnosis of heart disease and no previous antithrombotic therapy. The results of viscoelastic testing with the benchtop viscoelastic coagulation monitor (VCM Vet [VCM]; Entegrion) were compared between groups using factorial analysis of variance. RESULTS: Cats with heart disease had significantly higher clot times when compared to controls (control: mean, 285.3 [SD, 172.6]; CHF: mean, 391.7 [SD, 106.8]; ATE: mean, 415.9 [SD, 109.2]; and ATE plus CHF: mean, 368.6 [SD, 232.6]). Heart disease cats were noted to have significantly lower 45-minute lysis index values (control: median, 100 [range, 93 to 100]; CHF: median, 99 [range, 89 to 100]; ATE: median, 98 [range, 88 to 100]; and ATE plus CHF: range, 98 [91 to 100]). Age was a covariate to this variable, and when applied to analysis, statistical significance was lost. No significant difference in any other variables were noted. CLINICAL RELEVANCE: The hypercoagulability of ATE and CHF cats was not detected by the VCM. Further research with other coagulation monitors is required in this population.

Synchronized source of indistinguishable photons for quantum networks.

We present a source of indistinguishable photons at telecom wavelength, synchronized to an external clock, for the use in distributed quantum networks. We characterize the indistinguishability of photons generated in independent parametric down-conversion events using a Hong-Ou-Mandel interferometer, and show non-classical interference with coalescence, C = 0.83(5). We also demonstrate the synchronization to an external clock within sub-picosecond timing jitter, which is significantly shorter than the single-photon wavepacket duration of ≈ 35 ps. Our source enables scalable quantum protocols over multi-node, long-distance optical networks using network-based clock recovery systems.