Pd-Pt catalysts supported on carbon preheated to 1600°C have been reinvestigated in CHFCl2 hydrodechlorination. An additionally adopted catalyst oxidation at 350-400°C produced an order of magnitude increase in the catalytic activity of Pd/C. This increase is not caused by changes in metal dispersion or possible decontamination of the Pd surface from superficial carbon, but rather by unlocking the active surface, originally inaccessible in metal particles tightly packed in the pores of carbon. Burning carbon from the pore walls attached to the metal changes the pore structure, providing easier access for the reactants to the entire palladium surface. As upon calcination the performance of the rest of the Pd-Pt/C catalysts changes less than for Pd/C, the relation between the turnover frequency and alloy composition does not confirm the Pd-Pt synergy invoked in our previous work. The use of even higher-preheated carbon (1800°C), completely free of micropores, results in a Pd/C catalyst that does not need to be oxidized to achieve high activity and excellent selectivity up to CH2F2 (>90%).

This work aims to investigate the effect of Pt concentration on crystal growth mechanism of Platinum-Palladium (Pt-Pd) binary alloy system during the annealing process starting from amorphous phase until some definite temperatures. The calculations have been performed by using molecular dynamic (MD) simulations. Interatomic interactions are described by on Sutton-Chen type Embedded Atom Potential Energy function. In order to understand the main structural properties at the stable and unstable phases, changes in RDF curves versus time have been analysed for different annealing temperatures. Crystalline type bonded pairs have been determined using MD calculations which is required for the computation of Avrami coefficients and for understanding crystal growth mechanism. The results demonstrate that the increase in concentration of Pt during annealing leads to migration of atoms in the crystal lattice points, elimination of dislocations and formation of perfect crystal structure.

Organic light-emitting diodes (OLEDs) are energy-efficient; however, the coordinating ligand can affect their stability. Sky-blue phosphorescent Pt(II) complexes with a C^N chelate, fluorinated-dbi (dbi = [1-(2,4-diisopropyldibenzo[b,d]furan-3-yl)-2-phenyl-1H-imidazole]), and acetylactonate (acac)(1)/picolinate (pic)(2) ancillary ligands were synthesized. The molecular structures were characterized using various spectroscopic methods. The Pt(II) coordination sphere in 2 exhibited a distorted square-planar geometry, with several intra- and inter-molecular interactions involving Cπ⋯H/Cπ⋯Cπ stacking. Complex 1 emitted bright sky-blue light (λmax = 485 nm) with a moderate photoluminescent quantum efficiency of 0.37 and short decay time (6.1 µs) compared to those of 2. Time-dependent density functional theory calculations suggested that the electronic transition of 1 arose from ligand(C^N)-centered π–π* transitions combined with metal-to-ligand charge transfer transitions (MLCT), whereas that of 2 arose from MLCT and ligand(C^N)-to-ligand(pic) charge transfer (LLCT), with minimal contribution from the C^N chelate to the lowest unoccupied molecular orbital. Multi-layered phosphorescent OLEDs using 1 as a dopant and a mixed host, 3,3-di(9H-carbazol-9-yl)-1,1-biphenyl:3-di(9H-carbazol-9-yl)-1,1-biphenyl (mCBP)/9-(3’-carbazol-9-yl-5-cyano-biphenyl-3-yl)-9H-carbazole-3-carbonitrile (CNmCBPCN) were successfully fabricated. At a 10% doping of 1, a current efficiency of 13.6 cd A−1 and external quantum efficiency of 8.4 % at 100 cd m−2 were achieved. These results show that the ancillary ligand in phosphorescent Pt(II) complexes must be considered.

Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types, known for its suppressive effect on T cells through interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophil has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. An administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by increased plasma alanine transaminase (ALT) level and frequencies of inflammatory leukocytes in the liver implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities assisting in a smooth transition into the resolution phase in MRSA infection.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Cost-efficient catalyst for hydrogen evolution reaction (HER) and methanol oxidization reaction (MOR) is of great importance for industrial application. The alloying of platinum with cheap transition metal offers a great opportunity to reduce cost and enhance the electro-catalytic performance. Herein, we report a simple and green route to synthesize porous Pt-Cu catalysts, where Pt-Cu solid particles were first produced by using cuprous chloride (CuCl) nanoparticles as the template, followed by a dealloying treatment to obtain final porous product. The porous alloy nanoparticles show higher catalytic activity and superior stability for HER and methanol oxidation reaction, which is beneficial from the porous structure and synergetic effect between Pt and Cu.

In this work, Density Functional Theory (DFT) calculations were employed to study the photocatalytic CO2 to CO reduction by a series of Pt(II) square planar complexes with general formula [Pt(5-R-dpb)Cl] (dpb = 1,3-di(2-pyridyl)benzene anion, R = H, N,N-dimethylaniline,T thiophene, diazaborinine). The CO2 to CO conversion process is thought to proceed via two main steps, namely the photocatalytic/reduction step and the main catalytic step. The simulated absorption spectra exhibit strong bands in the 200 – 400 nm UV-Vis region. The calculated excited state reduction potentials are in the range 0.32 — -0.36 V revealing that the reductive quenching of the T1 state of the complexes could be modulated with suitable changes of the N^C^N pincer ligands. The CO2 fixation and activation by the ‘real’ three coordinated Pt(II) catalyst/intermediate is predicted to be favorable with Pt-CO2 bond dissociation energies, D0 in the range -36.9—-10.3 kcal/mol. The nature of the Pt-CO2 bond is complex with covalent, hyperconjugative and H-bonding interactions prevailing the repulsive electrostatic interactions. The main catalytic cycle is estimated to be a favorable exergonic process.

Aggressive mature T-cell lymphoma (TCL) is a disease that carries a poor prognosis. The mechanism, at the functional protein level, of the resistance to therapy of TCL has not yet been well clarified. To comprehensively clarify the mechanism, we first reviewed the literature, as mentioned in the Introduction section, on 22 types of representative functional proteins reported as being potentially associated with treatment resistance, mainly in hematologic tumors. Next, we retrospectively analyzed the tumor cell expressions of these 22 functional proteins in 16 randomly selected patients with TCL who had received CHOP (cyclophosphamide, hydroxyl doxorubicin, oncovin, and prednisolone) therapy as first-line treatment. As a result, we propose a new three-group prognostic classification of TCL (the TCL Urayasu Classification) based on the mechanism of resistance to treatment of these tumors. The study subjects included 7 patients (44%) with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 6 patients (38%) with angioimmunoblastic T-cell lymphoma (AITL), and 3 patients (19%) with anaplastic large T-cell lymphoma (ALCL). Immunohistochemistry was performed in paraffin-embedded tumor tissue sections prepared from these patients as antigens using antibodies against the 22 previously reported treatment-resistance-related proteins to determine the tumor cell expression statuses of these proteins. Log-rank test was performed to compare the overall survival (OS) after CHOP therapy of the patients showing positive and negative immunostaining for these proteins, as well as among patients grouped based on other factors. Overall, the median OS of the TCL patients was about 33.5 months. When compared by the disease type, the prognosis was found to be worse in the order of ALCL, AITL, and PTCL. A multivariate analysis showed that expression of glucose-regulated protein 94 (GRP94), a protein that serves as a pro-survival component under endoplasmic reticulum (ER) stress in the tumor microenvironment, was significantly associated with shortened survival. No significant difference was observed for the conventional poor prognostic factors: high-risk International Prognostic Index (IPI) and high-risk Prognostic Index for peripheral T-cell lymphoma, unspecified (PTCL-U) (PIT). However, when GRP94 was combined with six other factors, listed below, as survival-shortening factors, significant differences were observed. The 6 factors were 1) programmed cell death-ligand 1 (PD-L1) and 2) programmed cell death 1 (PD-1), which are involved in immune surveillance; 3) aldo-keto reductase family 1 member C3 (AKR1C3), which is an enzyme that inactivates HO (hydroxyl doxorubicin [H] and oncovin [O]) of CHOP; 4) P53, a tumor suppressor; 5) Glucose-regulated protein 78 (GRP78), an ER stress protein; 6) thymidine phosphorylase (TP), which is an enzyme involved in thymidine catabolism. Based on the combination of GRP94 and the six other factors expressed in the tumors, we propose a new prognostic classification system for TCL (TCL Urayasu classification). Group 1 (group with a relatively good prognosis): GRP94-negative (n = 6; median OS, 88 months; p < 0.01); Group 2 (group with a poor prognosis): GRP94-positive, plus expression of 2 of the 6 aforementioned factors (n = 5; median OS, 25 months; p > 0.05); and Group 3 (group with a very poor prognosis): GRP94-positive, plus expression of at least 3 of the 6 aforementioned factors (n = 5; median OS, 10 months; p < 0.01). Thus, the TCL Urayasu prognostic classification is a simple, useful, and innovative classification that also explains the mechanism of resistance to treatment for each functional protein. Accumulation of more cases and further analyses are expected in the future to enable clinical application, such as use of a stratified treatment approach and treatment using inhibitors.

Novel mechanism of ccRCC progression is essential, including PBRM1, BAP1, and SETD2 in histone-modifying and chromatin remodeling genes. The study aimed to investigate VHL, PD-1, PD-L1, PD-L2. BAP1, PBRM1, SETD2 expression in ccRCC primary cancers and metastatic tissues associated with the cancer dissemination. A total of 62 patients with RCC were enrolled in the study. Investigation of mRNA level of VHL, PD-1, PD-L1, PD-L2. PCR in real-time performed BAP1, PBRM1, SETD2 with the previous RNA isolation. Western Blotting analysis was used for detecting the p-VHL protein content in tissues. The VHL expression and p-VHL content determined the aggressive cancer behavior and elevated in disseminated tumors. The cancer dissemination was accompanied by an increase in both mRNA and VHL content. The PD-L2 prevalence in metastatic cancers is crucial in tumor progression. ccRCC progression in VHL overexpression is associated with the decrease in BAP1 gene expression. It is revealed the heterogeneity in molecular markers in primary tumors and metastases. The low mRNA level of BAP1, PBRM1, SETD2, PD-1, PD-L1, PD-L2 in metastases compared with primary tumors were found. We show a novel mechanism for VHL tumor progression and present a new instrument and factor targeting tumor-related pathologies with p-VHL/HIF altered function.

Soluble noble metal salts are widely used for loading noble metals as nano-catalysts in many applications. In this paper, Pt-SnO2 composite nanoceramics were prepared from SnO2 nanoparticles and H2PtCl6 using two Pt-loading methods separately: For the solution reduction method, the H2PtCl6 solution was added to a suspension of SnO2 and zinc powder to form Pt on SnO2 nanoparticles; and for the impregnation method, Pt was formed from H2PtCl6 in the course of sintering. Although a series of samples prepared using both Pt loading methods showed a strong response to H2 at room temperature, the ones prepared using the solution reduction method exhibited much better room temperature hydrogen sensing characteristics. For two samples of 0.5 wt% Pt and sintered at 825°C, the response value for the sample prepared using the solution reduction method was 5300 to 1% H2-20% O2-N2, which was much larger than that of 150 for the sample prepared using the impregnation method. Samples prepared using the two Pt loading methods have similar microstructures as characterized by XRD, FESEM, EDS, TEM, and HRTEM. However, the residual chlorine content in those using the impregnation method was found to be higher than that using the solution reduction method through analysis. It is proposed that the striking difference in the room temperature hydrogen sensing characteristics among samples prepared using these two different Pt loading methods separately resulted from their different chlorine removal process. This study demonstrates the importance of a proper method in loading noble metals from their soluble salts as nano-catalysts in many applications.

Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with CHOP (n=12) or CHOP plus APAVAC (n= 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

The meta hybrid M06-2X functional combined with the 6-311++G(d,p) basis set are used to investigate the antioxidant activity of five benzoic acid derivatives naturally occurring in several plant food: gallic acid, para-hydroxybenzoic acid, protocatechuic acid, syringic acid and vanillic acid. To assess the antioxidant properties of these compounds, three mechanisms of free radicals scavenging are considered, namely the hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) models. The effect of polar environments on the antioxidant power of these compounds is mimicked in water and methanol using the IEF-PCM solvation method. Our findings suggest that HAT is the preferred mechanistic pathway in gas phase, while SPLET is favoured in polar mediums. Protocatechuic and gallic acids are the most active in gas and polar solutions respectively, whereas PHBA is the least active in all the environments considered. The O-H group in para position of the carboxylic group (O3-H for GA and O2-H for the rest) is confirmed to be the most reactive site in gas phase, while in solution it is either of the O1-H site (for PHBA, PCA, SA and VA) or O4-H groups (for GA). The “HOMO-rule” of free radical scavenging ability does not seem to account properly for the antioxidant properties of this set of chemicals.

Diamond is a material with excellent performances which attracts the attention from researchers for decades. Pt (111), owing to its catalytic activity on diamond synthesis, is regarded to be a candidate for diamond hetero-epitaxity, which can enhance nucleation density. Molten surface at diamond growth temperature can also improve mobility and aggregation capability of primitive nuclei. Generally, (100)-oriented is welcomed for the achivement of high quality and large size diamond, since the formation of defects and twins are prevented. First-principle calculations and experimental researches were carried out for the study of transformation of orientation. The transformation from {111} to {100}-oriented diamond has been observed on Pt (111) substrate, which can be promoted by the increase of carbon source concentration and substrate temperature. The process is energetic favorable, which may provides a way towards large-scale (100) diamond films.

PD-1/PD-L1 axis is one key therapeutic target against tumor cell immune escape. Structurally essential to the PD-1/PD-L1-linked immune escape is the binding interface of the PD-1/PD-L1 complex structure. Incorporating currently available PD-1/PD-L1-related experimental structures, this article unveils two sets of experimentally observed inter-molecular electrostatic interactions which stabilize the binding interface of the PD-1/PD-L1 complex structure. For the first time, this article proposes an evolutionary structural hypothesis that, as a result of natural selection, PD-1 is able to genetically mutate itself to structurally disrupt the PD-1/PD-L1 axis towards the restoration of T cell-mediated anti-tumor immunity.

We investigate the dynamics and stationary states of a semiconductor exciton-polariton condensate in a double well potential. We find that upon the population build up of the polaritons by above-threshold laser pumping, coherence relaxation due to the phase fluctuations of the polaritons drives the system into a stable fixed point corresponding to a self-organized PT-symmetric phase.

Based on a modified dice-and-fill technique, a PIN-PMN-PT single crystal 1-3 composite with the kerf of 12 μm and pitch of 50 μm was prepared. The as-made piezoelectric composite material behaved with high piezoelectric constant (d33 = 1500 pC/N), high electromechanical coefficient (kt = 0.81), and low acoustic impedance (16.2 Mrayls). Using lithography and flexible circuit method, a 48-element phased array was successfully fabricated from such a piezoelectric composite. The array element was measured to have a central frequency of 20 MHz and a fractional bandwidth of approximately 77% at −6 dB. Of particular significance was that this PIN-PMN-PT single crystal 1-3 composite-based phased array exhibits a superior insertion loss compared with PMN-PT single crystal and PZT-5H-based 20 MHz phased arrays. The focusing and steering capabilities of the obtained phased array were demonstrated theoretically and experimentally. These promising results indicate that the PIN-PMN-PT single crystal 1-3 composite-based high frequency phased array is a good candidate for ultrasound imaging applications.

Background: PD1 and its ligand PD-L1 are related to the prognosis in many solid tumors, whether its role in oral squamous cell carcinoma (OSCC) remains unclear. Methods: Retrospective monocentric study including all patients with OSCC diagnosed and treated between 01/2020 and 05/2022. PD-L1 expression was assessed by combined positive score (CPS), considering CPS > or equal to 1 as positive (1-20 “low expression”, and ≥20 “high”). Descriptive analysis of patient cohort and tumors was performed, including tumor size, stage, lymph node involvement, recur-rence and survival. Results: 65 patients (65 tumors) were analyzed. 66.15% of tumors were ad-vanced stages (III-IV), of them, 97.67% PD-L1+ versus 71.42% within early stages (I-II). T4 tumors expressed PD-L1 in 100% of cases, compared with 54’54% in T1 tumors. 50.79 % of tumors showed lymph node involvement (pN+), 100% of them showing PD-L1+. Prevalence of pN+ was 59.38% for PD-L1 high expression versus 40.63% for low expression. Patients' follow-up ranged from 2 to 34.5 months. No significant difference was seen between overall survival (OS) and PD-L1 +/- (CPS ≥1 vs CPS <1) neither PD-L1 high (CPS ≥20) vs low CPS <20) (p 0.97 and 0.64, re-spectively). Conclusions: The method used to measure (laboratory test with Dako 22C3 an-ti-PD-L1 primary antibody) PD-L1 was reliable and accurate, with a correlation coefficient be-tween the PD-L1 expression in the biopsy and surgical piece of 0.83 (p 0.0001). CPS≥1 was ob-served in large tumors (p<0.001), and was correlated with of lymph node metastases (p<0.004). Further analysis of PD-L1 expression and its relevance in tumor biology and prognosis is needed.

Cancers of the brain and nervous system account for 1 in every 100 cancer diagnoses in the United States and about 0.3 million diagnoses globally, every year. Surgery, radiotherapy, and chemo-therapy constitute the standard of care. Despite advancements in diagnosis and treatment delivery, mortality rate for these cancers have remained steady for over three decades. Immunotherapy is an emerging fourth treatment modality which has been effective against several cancers but not brain cancers, such as glioblastoma, GBM. Here, we develop in vitro assays to quantify molecular readouts of cell death, cell migration and clonogenicity, and synopsize these as biophysical markers for the rapid evaluation of immune checkpoint inhibitors (ICI), durvalumab and pembrolizumab, alone and in combination with radiotherapy (radioimmunotherapy). We find different trends in their direct action on two GBM cell lines (T98G and U87), even in the absence of immune cells. Radiation alone, and pembrolizumab with radiation, both reduced (p < 0.05) cell-cell adhesion. This reduction suggests increased potential for local invasion. Our assays offer additional insights regarding ICIs, may enable evaluation of their potential efficacy, and could set the stage for pa-tient-specific radioimmunotherapy against brain cancers, engendering improved treatment out-comes.

Background: Recent researches have investigated the biological importance of RNA N1-methyladenosine (m1A) modifications in oncogenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, whether m1A modifications also have latent effect in tumor microenvironment (TME) generation and immune regulation in HNSCC is unknown. Methods: We evaluated the m1A modification patterns and related to these modification patterns with TME cell infiltration features in 1041 HNSCC samples by bioinformatics approach. Results: The m1A score is an independent prognostic indicator. HNSCC patients with low m1A score group with poor overall survival (OS) was mainly characterized by stroma activation, lack of sufficient immune infiltration, and exhibited an immune- desert TME phenotype. Low m1A scores were also correlated with increased tumor mutation burden (TMB), and HNSCC patients with high TMB and low m1A scores had the worst OS. In addition, anti-CTLA-4 combined with anti-PD1 treatment was more effective in the high m1A score subgroup than in the low m1A score subgroup. Conclusions: This study revealed that m1A modifications play a non-negligible role in developing the TME versatility and complexity of HNSCC. Assessing m1A modification patterns in HNSCC helps improve our comprehension of its TME infiltration profile and guides more effective immunotherapeutic approaches.

In this paper, we present a new concept of the generalized core orthogonality (called the C-S orthogonality) for two generalized core invertible matrices $A$ and $B$. $A$ is said to be C-S orthogonal to $B$ if $A^{\tiny\textcircled{S}}B=0$ and $BA^{\tiny\textcircled{S}}=0$, where $A^{\tiny\textcircled{S}}$ is the generalized core inverse of $A$. The characterizations of C-S orthogonal matries and the C-S additivity are also provided. And the connection between the C-S orthogonality and C-S partial order has been given using their canonical form. Moreover, the concept of the strongly C-S orthogonality is defined and characterized.

Lymph nodes are secondary lymphoid organs that appear as bean-like nodules usually <1 cm in size, and they are localized throughout the body. Many antigen-presenting cells such as dendritic cells and macrophages reside in lymph nodes, where they mediate host defense responses against pathogens such as viruses and bacteria. In cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs) to react to cancer cell–derived antigens. Macrophages located in the lymph node sinus are of particular interest in relation to anti-cancer immune responses because many studies using both human specimens and animal models have suggested that lymph node macrophages play a key role in activating anti-cancer CTLs. The regulation of lymph node macrophages therefore represents a potentially promising novel approach in anti-cancer therapy.

The advent of immunotherapy has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), improving the prognosis of this disease and becoming a key part of the treatment, especially in the population without an oncogenic driver mutation. Two different groups of immune checkpoint inhibitors (ICIs) are used in lung cancer: Anti- Cytotoxic T-lymphocyte antigen-4 (Anti-CTLA 4) and Anti- T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti PD-L1). Here in, we review an uptodate on the use of immunotherapy for advanced NSCLC.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Cellular immunotherapy has recently emerged as a fourth pillar in cancer treatment co-joining surgery, chemotherapy and radiotherapy. Where, the discovery of immune checkpoint blockage or inhibition (ICB/ICI), anti-PD-1/PD-L1 and anti-CTLA4-based, therapy has revolutionized the class of cancer treatment at a different level. However, still some cancer patient escape this immune surveillance mechanism and become resistant to ICB-therapy. Therefore, a more advanced or an alternative treatment is required instantly. Despite the functional importance of epitranscriptomics in diverse clinico-biological practices, its role in improving the efficacy of ICB therapeutics has been limited. Consequently, our study encapsulates the evidences, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which could be reformed into RNA modifying drugs (RMD). Here, we have explained the mechanism of individual RNA-modifiers (editor/writer, eraser/remover and effector/reader) in overcoming the issues associated with high-dose antibody toxicities and drug-resistance. Moreover, we have shed light on the importance of suppressor of cytokine signalling (SOCS/CISH) and microRNAs in improving the efficacy of ICB-therapy, with brief insight on the current monoclonal antibodies undergoing clinical trials or already approved against several solid tumor and metastatic cancers. We anticipate our investigation will encourage researchers and clinicians to further strengthen the efficacy of ICB-therapeutics by considering the importance of epitranscriptomics as a personalized medicine.

The regulation of multiple bacterial phenotypes was found to depend on different cyclic di-nucleotides (CDNs) that constitute intracellular signalling second messenger systems. Most notably, c-di-GMP, along with proteins related to its synthesis, sensing and degradation, was identified as playing a central role in the switching from biofilm to planktonic modes of growth. Recently, this world has been under expansion, with the discoveries of other signalling CNDs in bacteria (c-di-AMP and cGAMP) and also in eukaryotes, novel protein and RNA receptors of CDNs, and the numerous functions related to these molecules. In this work, we comprehensively review and analyse the structural biology data about the systems that bacteria use to synthesise and recognise CDNs, detailing their interactions at molecular level with their products/ligands. Additional interesting observations were made, including that different receptor types can bind CDNs in similar conformations and that, based on genomic data, different CDN second messenger systems may coexist in many organisms. The large amount of sequence and structural data available allows a broad view of the importance of CDNs in bacteria, but how cells coordinate these molecules to ensure adaptation to changing environmental conditions is still open for much further exploration.

Polychlorinated phenoxathiins (PCPTs), polychlorinated dibenzothiophenes (PCDTs), and polychlorinated thianthrenes (PCTAs) are sulfur analogues of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/DFs). Chlorothiophenols(CTPs) and chlorophenols (CPs) are key precursors to form PCTA/PT/DTs, which can form chloro(thio)phenoxy radical, sulfydryl/hydryl-substituted phenyl radical and (thio)phenoxyl diradicals. The available radical/radical PCTA/DT formation mechanism failed to explain the higher concentration of PCDTs than that of PCTAs under the pyrolysis or combustion conditions. Thus in this work, a detailed thermodynamics and kinetic calculations were carried out to investigate the pre-intermediates formation for PCTA/PT/DTs from radial/molecule coupling of 2-C(T)P with their key radical species. Our study found that the radial/molecule mechanism can thermodynamically and kinetically contribute to the gas-phase formation of PCTA/PT/DT/s. The S/C coupling modes to form thioether-(thio)enol intermediats are preferable over the O/C coupling modes to form ether-(thio)enol intermediats. Thus, although the radial/molecule coupling of chlorophenoxy radical with 2-C(T)P have no effect on the PCDD/PTs formation, the radial/molecule coupling of chlorothiophenoxy radical with 2-C(T)P play an important role in the PCDT/PT formation. Most importantly, the pre-PCDT intermediates formation pathways from the coupling of sulfydryl/hydryl-substituted phenyl radical with 2-C(T)P and the coupling of (thio)phenoxyl diradicals with 2-C(T)P are more favorable to pre-PCTA/PT intermediates formation pathways from the coupling of chlorothiophenoxy radical with 2-C(T)P, which can give reasonable explanation for the high PCDT-to-PCTA ratio in the environment.

The approval of monoclonal antibodies against programmed death-ligand 1 (PD-L1) and programmed cell death protein (PD1), has changed the landscape of cancer treatment. To date, many Immune Checkpoint Inhibitors (ICIs) have been approved by the FDA for the treatment of metastatic cancer as well as locally recurrent advanced cancer. However, immune-related adverse events (irAEs) of ICIs highlight the need for biomarker analysis with strong predictive value. Liquid biopsy is an important tool for clinical oncologists to monitor cancer patients and administer or change appropriate therapy. CTCs frequently express PD-L1 and this constitutes a clinically useful and non-invasive method to assess PD-L1 status in real time. This review summarizes all the latest findings about the clinical significance of CTC for the management of cancer patients during administration of immunotherapy and mainly focuses on the assessment of PD-L1 expression in CTCs.

In this study the processes taking place on the surfaces of nanostructurized Cu/CuO and Cu/CuO/Pd electrodes at different potential, $E$, values in the solutions of 0.1 M KOH in H$_2$O and D$_2$O (heavy water) were probed by the surface enhanced Raman spectroscopy (SERS) and analysis of electrochemical reactions occurring under experimental conditions is presented. Bands of the SERS spectra of Cu/CuO/Pd electrode observed in the range of $E$ values from +0.3~V to 0 V~(SHE) at 1328 - 1569~cm$^{-1}$ are consistent with the existence of species which are adsorbed or weakly bound to the surface with the energy of interaction close to 15 - 21~kJ mol$^{-1}$. These bands can be attributed to the ad(ab)sorbed (H$_3$O$^+$)$\rm{_{ad}}$, (H$_2^+$)$\rm{_{ab}}$ and (H$_2^+$)$\rm{_{ad}}$ ions as intermediates in reversible HER/HOR processes taking place on Cu/CuO/Pd electrode. There was no isotopic effect observed; this is consistent with a dipole nature of electron-ion pair formation of adsorbed (H$_3$O$^+$)$\rm{_{ad}}$ and (H$_2^+$)$\rm{_{ad}}$ or (D$_3$O$^+$)$\rm{_{ad}}$ and (D$_2^+$)$\rm{_{ad}}$. In accordance with literature data SERS bands at 125-146~cm$^{-1}$ and $\sim 520-565$~cm$^{-1}$ were assigned to Cu(I) and Cu(II) oxygen species. These findings corroborate the mechanism of cascading reduction of water.

Lung cancer remains the leading cause of cancer-related death and it is usually diagnosed in advanced stages (stage III or IV). Recently, the availability of targeted strategies and of immunotherapy with checkpoint inhibitors (ICI) has favorably changed patient prognosis. Treatment outcome is closely related to tumor biology and interaction with the host immune microenvironment (TME). Whether for targeted therapies the response relies on the presence of specific genetic alterations in tumor cells, for ICI accurate biomarkers of response are lacking and clinical outcome likely depends on multiple factors, host and tumor-related. This paper is an overview of the ongoing research on predictive factors both from in-vitro/ex-vivo analysis (ranging from conventional pathology to molecular biology) and in-vivo analysis, where molecular imaging is showing an exponential growth and use due to the technological advancement and to the new bioinformatics approaches applied to image analyses that allow specific features recovery in specific tumor subclones.

Higher body weight is known to negatively impact plasma vitamin C status. However, despite this well-documented inverse association, recommendations on daily vitamin C intakes by health authorities worldwide do not include particular reference values for people of higher body weight. This suggests that people of higher body weight and people with obesity may be insufficient in vitamin C in spite of ingesting the amounts recommended by their health authorities. The current preliminary investigation sought to estimate how much additional vitamin C people with higher body weights need to consume in order to attain a comparable vitamin C status to that of a lower weight person consuming an average Western vitamin C intake. Data from two published vitamin C dose-concentration studies were used to generate the relationship: a detailed pharmacokinetic study with seven healthy non-smoking men and a multiple depletion-repletion study with 68 healthy non-smoking men of varying body weights. Our estimates suggest that an additional intake of 10 mg vitamin C/day is required for every 10 kg increase in body weight to attain a comparable plasma concentration to a 60 kg individual with a vitamin C intake of ~110 mg/day, which is the daily intake recommended by the European Food Safety Authority (EFSA). Thus, individuals weighing e.g. 80 and 90 kg will need to consume ~130 and 140 mg vitamin C/day, respectively. People with obesity will likely need even higher vitamin C intakes. As poor vitamin C status is associated with increased risk of several chronic diseases including cardiovascular disease, these findings may have important public health implications. As such, dose-finding studies are required to determine optimal vitamin C intakes for overweight and obese people.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.

Background/Aim: To evaluate the association between baseline [18F]FDG-PET/CT tumor burden parameters and disease progression rate after first-line target therapy or immunotherapy in advanced melanoma patients. Materials and Methods: 44 melanoma patients who underwent [18F]FDG-PET/CT before first-line target therapy (28/50) or immunotherapy (16/50) were retrospectively analyzed. Whole-body and per-district metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. Therapy response was assessed according to RECIST 1.1 on CT scan at 3 (early) and 12 (late) months. PET parameters were compared with Mann-Whitney test. Optimal cut-offs for predicting progression were defined using the ROC curve. PFS and OS were studied using Kaplan-Meier analysis. Results: Median(IQR) MTVwb and TLGwb were 13.1 mL and 72.4 respectively. Non-responders patients were 38/44, 26/28 and 12/16 at early evaluation, and in 33/44, 21/28 and 12/16 at late evaluation in the whole-cohort, target and immunotherapy subgroup respectively. At late evaluation, MTVbone and TLGbone were higher in non-responders compared to responder patients (all p<0.037) in the whole-cohort and target subgroup and also MTVwb and TLGwb (all p<0.022) in target subgroup. No significant differences were found for immunotherapy subgroup. No metabolic parameters were able to predict PFS. Controversy, MTVlfn, TLGlfn, MTVsoft+lfn, TLG-soft+lfn, MTVwb and TLGwb were significantly associated (all p<0.05) with OS in both the whole-cohort and target therapy subgroup. Conclusion: Higher values of whole-body and bone metabolic parameters were correlated with poorer outcome, while higher values of whole-body, lymph node and soft tissue metabolic parameters were correlated with OS.

Tissue programmed death ligand-1 (PD-L1) protein is the recognized predictive immune biomarker of immune checkpoint inhibitor (ICI) treatment benefit in metastatic non-small cell lung cancer (NSCLC). However, tissue PD-L1 protein testing can be limited by tumor heterogeneity and fraught with tissue acquisition difficulties. A plasma PD-L1 assay potentially overcomes these tissue limitations. Patients with metastatic NSCLC treated with first-line ICI-based treatment and available results of plasma cfRNA PD-L1 by real-time polymerase chain reaction (RT-PCR) and tissue PD-L1 protein PD-L1 with the Dako 22C3 monoclonal antibody were retrospectively assessed for median and landmark 3-year overall survival (OS). OS was identical whether positive plasma cfRNA PD-L1 expression or positive tissue PD-L1 protein expression (median OS 15 months; 3-year landmark OS 30%; hazard ratio (HR) 0.97; 95% CI, 0.44-2.10). Positive plasma cfRNA PD-L1 patients also demonstrated a numerically longer median and higher 3-year OS compared to patients lacking PD-L1 expression (median 15 months versus 8 months; 3-year landmark OS 30% versus 15%; HR 0.56; 95% CI, 0.27-1.17). Plasma cfRNA PD-L1 expression by RT-PCR was similarly predictive of ICI-based treatment benefit as tissue PD-L1 protein expression.

Penile squamous cell carcinoma (SCC) is a rare disease. Treatment options for advanced penile cancer are often limited and prognosis remains poor. We reported a 52-year-old male recurrent and metastatic penile SCC patient with high PD-L1 expression(90%) and TMB(14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection and excision of the abdominal wall mass during two surgeries. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin were then carried out, the carcinoma still had progressed. The patient then obtained progression free survival exceeding 32 months with continuous sintilimab, although new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He didn’t have positive type 1 diabetes associated autoantibodies, but had susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory penile SCC obtained remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab.

Background; Programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1) are target molecules for immunotherapy in non-small cell lung cancer. PD-L1 is expressed not only in cancer cells, but also on macrophages, and has been suggested to contribute to macrophage-mediated immune suppression. Methods; Clinical significance of PD-L1 expression on macrophages in human lung adenocarcinoma was examined. The mechanisms of PD-L1 overexpression on macrophages were investigated by means of cell culture studies. Results; High PD-L1 expression on macrophages was correlated with the presence of EGFR mutation, a lower cancer grade, and a shorter cancer-specific overall survival. In an in vitro study using lung cancer cell lines and human monocyte-derived macrophages, the conditioned medium from cancer cells was found to up-regulate PD-L1 expression on macrophages via STAT3 activation, and a cytokine array revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) was a candidate factor that induced PD-L1 expression. Culture studies using recombinant GM-CSF, neutralizing antibody, and inhibitors indicated that PD-L1 overexpression was induced via STAT3 activation by GM-CSF derived from cancer cells. Conclusions; PD-L1 overexpression on macrophages via the GM-CSF/STAT3 pathway was suggested to promote cancer progression in lung adenocarcinoma. Cancer cell-derived GM-CSF might be a promising target for anti-cancer therapy.

Herein, we report about the monometallic Ni and bimetallic Pd-Ni catalysts supported on CeO2-Al2O3 binary oxide, which were investigated in oxy-steam reforming of methanol (OSRM). Monometallic and bimetallic supported catalysts were prepared by wet aqueous impregnation and subsequent impregnation method, respectively. The physicochemical properties of the catalytic systems were investigated using various methods such as: BET, XRD, TPR-H2, TPD-NH3, XPS and SEM-EDS techniques. It has been proven that the addition of palladium to the nickel catalyst facilitates its reduction. The activity tests performed for all catalysts confirmed the promotion effect of palladium on catalytic activity of nickel catalyst and selectivity towards hydrogen production. Both nickel and bimetallic palladium-nickel supported catalysts showed excellent stability during the reaction. Such catalytic systems are valuable for the advance of the field of fuel cell technology.

A super-porous hybrid platform can offer significantly increased number of reaction sites for the analytes and thus can offer advantages in the biosensor applications. In this work, a significantly improved sensitivity and selectivity of hydrogen peroxide (H2O2) cancer sensor is demonstrated by a super-porous hybrid CuO/Pt NP platform. The super-porous hybrid platform is fabricated by a physiochemical approach combining the physical vapor deposition of Pt NPs and electrochemical deposition of super-porous CuO structures by adopting a dynamic hydrogen bubble technique. Under an optimized condition, the hybrid CuO/Pt biosensor demonstrates a very high sensitivity of 2,205 µA/mM∙cm2 and a low limit of detection (LOD) of 140 nM with a wide range of H2O2 detection. This is meaningfully improved performance as compared to the CuO-based H2O2 sensors as well as to the previously reported metal oxide based H2O2 sensors. The hybrid CuO/Pt platform exhibits excellent selectivity against other interfering molecules such as glucose, fructose, dopamine, and ascorbic acid. Due to the synergetic effect of highly porous CuO structures and underlying Pt NPs, the CuO/Pt architecture offers extremely abundant active sites for the H2O2 reduction and electron transfer pathways.

IHepatitis C virus (HCV) has a high genetic diversity, with seven genotypes with 86 subtypes. This genetic variability confers persistence in the infection and escape of the immune system with evolution to cirrhosis and cancer. Environmental factors can contribute to different disease progression, being essential to assess the viral genotype in the infection and discuss the environmental particularities of Eastern Amazon, and the frequencies of Liver fibrosis between different HCV genotypes in patients living in a region of the Brazilian Eastern Brazilian Amazon. Consists in an observational cross-sectional study. Sociodemographic and clinical data of 76 individuals diagnosed with Hepatitis C between 2019 and 2020 in public health services were selected. Data collected was tabulated in Microsoft Excel 2010TM spreadsheets and analysed in GraphPad Prism 5.0TM. Liver fibrosis was associated with genetic subtypes. Subtype 1b was predominant (42.1%), followed by 1a (13%) and 3a (1.3%). 69.7% of participants had chronic hepatitis, with mild fibrosis (F1/F2) being the most prevalent (38.1%). Severe fibrosis was detected in 75% of individuals infected with the subtype 1b, that is associated with more severe disease. We suggest further studies, to assess other communities in the region, as well as the monitoring of these patients with Liver Elastography to determine the disease evolution and its better management.

This work demonstrates that a plasmid can function as an efficient biocatalyst in mediating the nitroaldol (Henry) reaction at high temperatures in ultrapure water. Compared with ssDNA, the plasmid displayed a remarkable catalytic efficiency (97% yield within 20 min). Aromatic aldehydes which bear strong or moderate electron-withdrawing groups reacted satisfactorily with nitromethane, which afforded the corresponding β-nitroalcohols in good yields within 2 h (up to 98%). By contrast, aliphatic and aromatic aldehydes with electron-donating groups did not react. Moreover, the yield significantly dropped when the size of the carbanion increased, and the yield was only 10% when nitropropane was used as the donor.

Patients diagnosed with unresectable locally advanced Triple Negative Breast Cancer (TNBC) usually have poor outcome for its aggressive clinical behaviour. Atezolizumab plus nanoparticle albumin-bound (nab)-Paclitaxel prolonged progression-free survival (PFS) and overall survival (OS) among patients with unresectable locally advanced TNBC but its use is hampered by the lack of reliable predictors of tumor response. Seventy-seven consecutive patients with unresectable locally advanced TNBC treated with Atezolizumab plus nab-Paclitaxel were studied by blood draws at baseline, 28 days and 56 days after initiation of treatment. Exosomal PD-L1 mRNA in plasma was determined using Bio-Rad QX100 digital droplet PCR system and exoRNeasy kit and objective responses were defined following the RECIST criteria v.1.1. The study evaluates whether PD-L1 mRNA copies per ml in plasma-derived exosomes may predict response to anti-PD-L1 antibodies early in the course of therapy. Our data showed patients with unresectable locally advanced TNBC and higher levels of PD-L1 mRNA expression in plasma-derived exosomes at baseline demonstrated greater response to atezolizumab plus nab-paclitaxel. Furthermore, the levels of mRNA decreased with successful treatment while the copy number increased in patients experiencing disease progression following atezolizumab plus nab-paclitaxel. For the first time, our data showed the usefulness of assessment of exosomal PD-L1 as non-invasive real-time biopsy in patients diagnosed with TNBC suggesting exosomal PD-L1 is significantly associated with outcome and response to Atezolizumab plus nab-Paclitaxel.

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using immunohistochemical analysis of the expression of anti-gens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells, and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET, in general, is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers) able to identify specific immune system targets are under investigation in pre-clinical and clinical settings. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells, and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).

This study aims at investigating the catalytic performance of Pd, Pd/Pt, and Pd/Au nanocatalysts toward the 2-propanol electro-oxidation reaction (2POR) in an alkaline medium. The catalyst components (Pd, Pt, and Au) were sequentially electrodeposited onto a glassy carbon (GC) electrode surface and further characterized using electrochemical (cyclic voltammetry (CV)) and materials (Field-emission scanning electron microscopy (FE-SEM) coupled with energy dispersive X-ray (EDX)) characterization methods. The Pd/Au/GC catalyst showed the highest catalytic activity in terms of the highest oxidation current (0.386 mA) and the highest stability in terms of the highest obtained current after 1800 s of continuous electrolysis. This behaviour was attributed to the enhancement in the charge transfer kinetics where the Pd/Au/GC catalysts acquired the lowest charge transfer resistance (Rct, 1.85 kΩ) during the 2POR.

Aim: to provide a comprehensive overview of the existing literature concerning the applications of positron emission tomography (PET)-radiomics in lung cancer patients candidates or undergoing immunotherapy. Materials and Methods: A systematic review was conducted on databases and web sources. English-language original articles were considered. The title and abstract were in-dependently reviewed to evaluate study inclusion. Papers duplicate, out-of-topic, review or edi-torials articles and letters to editors were excluded. For each study, the radiomics analysis was assessed based on the relies on radiomics quality score (RQS 2.0). The review was registered on the PROSPERO database with the number CRD42023402302. Results: 15 papers were included, 13 were qualified as conventional radiomics approaches, and two were as Deep Learning radiomics. The content of each study was different, indeed, 7 papers investigated the potential role of radiomics to predict PD-L1 expression and tumor microenvironment before starting immunotherapy. Moreo-ver, 2 were relative to the prediction of response and 4 investigated the utility of radiomics to predict the response to immunotherapy. Finally, 2 papers were relative to the prediction of adverse events due to the immunotherapy. Conclusions: radiomics is promising in the evaluation of TME and for the prediction of response to immunotherapy, but some limitations should be overpassed.

Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise“ or “personalized“ enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

Due to the widespread application of (hetero)arylazoles, the development of straightforward functional group-tolerant synthetic methods that enable selective heteroaromatic elaboration under mild conditions aroused considerable attention. Over the last years we were interested in studies aimed to broaden the substrate scope of the direct functionalization of azoles and, in particular, to develop efficient synthetic protocols for the carbon-carbon bond forming reaction by selective palladium-catalyzed Csp2-H bond activation of imidazole derivatives. During these studies, we discovered that the outcome of the Pd-catalyzed arylation of imidazoles with aryl bromides is deeply influenced by the nature of the reaction solvent. Specifically, it is well known that the Pd-catalyzed direct arylation of imidazoles with aromatic halides selectively leads to C-5 monoarylation products when polar aprotic solvents such as DMF (or DMA) are used as a reaction medium, but these solvents are coded as dangerous according to EHS (Environmental, Health, Safety) parameters. Instead, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. So, with the intention of filling this gap, in this paper, we have developed a selective C-5 arylation procedure in anisole as the solvent, discovering also the unprecedented role of benzoic acid as a promoter of the coupling.

The α(1,2)fucosyltransferase (Se enzyme) encoded by FUT2 is involved in the secretor status of ABH(O) blood group antigens. The sedel2 allele is one of the non-functional FUT2 (se) alleles in which 9.3 kb containing the entire coding region of FUT2 is deleted by Alu-mediated nonhomologous recombination. In addition to this allele, three SNPs of FUT2, c.375A>G, c.385A>T, and c.571C>T, appear to be prevalent in certain Oceanian populations such as Polynesians. Recently, we developed an endpoint genotyping assay to determine the sedel2 zygosity, using a FAM-labeled probe for detection of the sedel2 allele and a VIC-labeled probe for detection of FUT2. In this study, instead of the VIC probe, a HEX-labeled probe covering both c.375A>G and c.385A>T and a Cy5-labeled probe covering c.571C>T were added to the sedel2 allele assay mixture to allow simultaneous detection of these four variations by endpoint genotyping for the sedel2 zygosity and fluorescence melting curve analysis for c.375A>G, c.385A>T, and c.571C>T genotyping. The results obtained from 24 Samoan subjects with this method were identical to those obtained with previous methods. Therefore, it appears that present method can accurately determine these four variations simultaneously.

The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. It may be possible for us to use programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of CA patients and their response to ICI therapy. The levels of the PD-1, PD-L1, and CD8 proteins were analyzed by immunohistochemical analysis from formalin-fixed, paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed by the Kaplan–Meier method and univariate and multivariate Cox proportional hazard regression model. We observed a significant inverse-correlation between the PD-1 and CD8 expression (p=0.001, chi square test). We also found a significant inverse-correlation between the PD-L1 and CD8 expression (p=0.027). The overall survival was significantly worse in patients with positive PD-1 expression (p=0.027). Similarly, the progression-free survival was also worse (p=0.087). Our results demonstrate that a high level of PD-1 expression is associated with a poor prognosis in CA patients. Further research is necessary to identify the molecular mechanisms that mediate this association.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to interrogate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations and the possible extent of these additional requirements. The relevant data were extracted from the NHANES 2017-2018 datasets, the final cohort of which comprised 2828 non-supplementing adult males and females (aged 18 – 80+ years) with both vitamin C serum concentrations and dietary intake data available. The data was subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: &gt;3.0, 1.36 – 3.0, ≤1.35), weight tertiles (≤72, 72-91, ≥91 kg), BMI tertiles (≤26, 26-32, ≥32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach ‘adequate’ serum concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heaver weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes &gt; 75 mg/day, at intakes &lt; 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population must consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach the same vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs 56 ± 24 µmol/L, P <0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs 24 ± 14 µmol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.

Candida (C.) infections represent a serious health risk for people affected by inflammatory bowel disease. An important fungal virulence factor is the capacity to form biofilms on the colonized surface of the host. This research study aimed to determine the effect of C. tropicalis and C. albicans co-infection on dextran sodium sulfate (DSS)-induced colitis in mice. Colitis severity was evaluated using histology and colonoscopy. Mice were mono-inoculated with C. albicans, C. tropicalis or co-challenged with both species. Mice were administered 3% DSS to induce acute colitis. Biofilm activity was assessed using (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] 2H-tetrazoliumhydroxide (XTT) assay. Abundance of C. albicans in the colon tissues was assessed by immunohistochemistry. Co-challenged mice showed decreased colitis severity compared to mono-inoculated mice. The XTT assay demonstrated a marked decrease of C. albicans biofilm production in a C. albicans culture incubated with C. tropicalis supernatant. Immunohistochemical staining showed that C. albicans was more abundant in the mucosa of C. albicans mono-inoculated mice compared to the co-inoculated group. These data indicate an antagonistic microbial interaction between the two Candida species, where C. tropicalis may produce molecules capable of limiting the ability of C. albicans to adhere to the host intestinal surface leading to a reduction in biofilm formation.

Background and objectives: Since 2013, highly effective direct-acting (DAA) chronic hepatitis C (CHC) antiviral therapy became available, which has cure rates of over 95%. For choice of optimal CHC treatment, assessment of hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage are necessary. Information about distribution of these parameters among CHC patients in Baltic states and especially in Ukraine is scarce. This study was performed to obtain epidemiological data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (Baltic states) and lower-middle income (Ukraine) countries. Materials and Methods: This was an epidemiological, retrospective, cross-sectional study that included 1451 CHC patients. Demographic and disease information from medical charts was collected for each patient during a single visit. Results: Most frequent suspected mode of viral transmission was blood transfusions (17.8%), followed by injection drug use (15.7%); however, in 50.9% of patients exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%) transmission by the injection drug use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1 - 66.4%; GT3 - 28.1; and GT2 - 4.1%. The prevalence of GT1 was the highest in Latvia (84%), and the lowest in Ukraine (63%, p<0.001). Liver fibrosis stages were distributed as follows: F0 - 12.2%, F1 - 26.3%, F2 - 23.5%, F3 – 17.1% and F4 - 20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p <0.001). Conclusions: This study contributes to the knowledge of epidemiological characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.

Background: Angelica gigas Nakai, Korean dang-gui, has long been widely used in traditional treatment methods. There have been a number of studies of the health effects of A. gigas and related compounds, but studies addressing effects on blood triglycerides (TG) are lacking. To investigate the effects of A. gigas Nakai extract (AGNE) on TG in Korean subjects, we carried out a 12-week, randomized, double-blind, placebo-controlled clinical trial. Methods: Subjects who met the inclusion criterion (130 mg/dL ≤ fasting blood TG ≤ 200 mg/dL) were recruited for this study. One hundred subjects were assigned to the AGNE group (n=50) or the placebo group (n=50), who were given 1g/day of AGNE (as a gigas Nakai extract 200mg/d) in capsules, and the control group for 12 weeks. Outcomes were efficacy TG, lipid profiles, atherogenic index, and safety parameters were assessed initially for a baseline measurement and after 12 weeks. Results: After 12 weeks of supplementation, TG and very low-density lipoprotein cholesterol (VLDL-C) concentration and TG/HDL-C ratio in the AGNE group were significantly reduced compared to the placebo group (p <0.05). No significant changes in any safety parameter were observed. Conclusions: These results suggest that ingestion of AGNE may improve TG and be useful to manage or prevent hypertriglyceridemia.

To realize high response and selectivity gas sensor in detecting dissolved gases in transformer oil, in this study, the adsorption of four kinds of gases (H2, CO, C2H2 and CH4) on Pd-graphyne as well as the gas sensing properties evaluation were investigated. The energetically favorable structure of Pd doped γ-Graphyne was first studied, including the comparison of different adsorption sites and discussion of electronic properties. Then, the adsorption of these four molecules on Pd-graphyne was explored. The adsorption structure, adsorption energy, electron transfer and electron distribution, the band structure and density of states were calculated and analyzed. The results show that the Pd atom prefers to be adsorbed on the middle of three C≡C bonds and the band gap is smaller. The CO adsorption exhibits the largest adsorption energy and electron transfer and brings obvious change to the structure and electron properties to Pd-graphyne. Because of the conductance decrease after adsorption CO and acceptable recovery time at high temperature, the Pd-graphyne can be promising gas sensing materials to detect CO with high selectivity. This work offers theoretical support for the design of nanomaterials based gas sensor using novel structure for industrial application.

NaoMaiTong (NMT: Radix et Rhi-zoma Rhei, Radix Ginseng, Radix Puerariae, and Rhizoma Ligustici Chuanxiong as 9: 9: 6: 6) is a traditional Chinese medicine prescription for treating ischemia cerebral apoplexy. In this work, four cell injury models of ischemic stroke were establish, namely hypoxic injury, glutamate damage, injury of potassium chloride and hydrogen peroxide damage model. The protective effects of NMT and its single herbs-containing sera of different time points on PC12 cell damage were evaluated respectively, and the corresponding efficacy-time curves were drawn. Cell viability was measured by MTT (3-(4,5)-Dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide) assay. Furthermore, an statistical methods of support vector machine (SVM) were used to establish the correlation between concentration-time-efficacy for the first time. These results revealed that NMT-containing serum has obvious protective effect on the four injury models and can significantly improve cell viability. The PK-PD correlation between fifteen ingredients in the NMT compound with four model efficacy indexes indicated that rhein, puerarin, and 3'-methoxy puerarin might be the most important constituents controlling the pharmacological effects of NMT. The study suggested that these fifteen components are likely to be the material basis of NMT and recommended to increase the amounts of Pueraria in the NMT compound. That provided the scientific basis and demonstration for the research of efficacy material base of Traditional Chinese Medicine (TCM).

A scientific consensus is emerging on the benefits of dc distribution in medium voltage power systems of ships and cities. At least 50% space savings and increased power transfer capacity are estimated with enhanced voltage dc operation of electric cables. The goal of this research is to contribute to developing the empirical knowledge on the insulation performance in order to validate the feasibility of such anticipated gains of dc versus ac, and to determine the comparative impact of different operational conditions from a component engineering point of view. The partial discharge (PD) activity in cables is measured under ac and dc conditions as an indicator of insulation performance. Specifically, PDs in defects at the semicon-insulation interface are studied in terms of inception voltage, repetition rate and discharge magnitude. Empirical understanding is drawn for operating voltage and frequency dependence of the discharge behavior in such voids in the range of 10 to 20\,kV and 0 to 0.1\,Hz, respectively. The change in PD activity with void evolution is explored.

Copper-catalyzed and organocopper-involved reactions are of great significance in organic synthesis. To have a deep understanding of the reaction mechanisms, the structural characterizations of organocopper intermediates become indispensable. Meanwhile, the structure-function relationship of organocopper compounds would advance rational design and development of new Cu-based reactions and organocopper reagents. Compared to the mono-carbonic ligand, the C,N- and C,C-bidentate ligands better stabilize the unstable organocopper compounds. The bidentate ligands can chelate to the same copper atom via ?2-mode, forming a mono-cupra-cyclic compounds with at least one acute C-Cu-C angle. When the bidentate ligands bind to two copper atoms via ?1-mode at each coordinating site, the bimetallic macrocyclic compounds will form nearly linear C-Cu-C angles. The anionic coordinating sites of the bidentate ligand can also bridge two metals via ?2-mode, forming organocopper aggregates with Cu-Cu interactions and organocuprates with contact ion pair structures. The reaction chemistry of some selected organocopper compounds is highlighted, showing their unique structure-reactivity relationships.

Preterm delivery can be precipitated by infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. 90 infants had suspected prenatal infection and 63 were diagnosed with postnatal infection. Independent of gestational age at delivery, MCP-1 was significantly increased (P &lt; 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (P&lt;0.01) and CRP was increased (P&lt;0.05) in the presence of chorioamnionitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age. In those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants born exclusively for maternal indications.

Motivated from the theory of Hilbert-Schmidt morphisms between Hilbert C*-modules over commutative C*-algebras by Stern and van Suijlekom [J. Funct. Anal., 2021], we introduce the notion of p-absolutely summing morphisms between Hilbert C*-modules over commutative C*-algebras. We show that an adjointable morphism between Hilbert C*-modules over monotone closed commutative C*-algebra is 2-absolutely summing if and only if it is Hilbert-Schmidt. We formulate version of Pietsch factorization problem for p-absolutely summing morphisms and solve partially.

A series of MgAl-layered double hydroxide (MgAl-HT), the calcined form at 500^oC (MgAlO_x) and the re-hydrated one at 25^oC (MgAl-HT-RH) were synthesized. Physicochemical properties of the catalysts were characterized by x-ray diffraction (XRD), scanning electron microscopy (SEM). Surface area of the as-synthesized, calcined and re-hydrated catalysts was determined by N₂ physisorption at -196^oC. CO₂-teperature programmed desorption (CO₂-TPD) was applied to determine the basic sites of catalysts. The catalytic test reaction was carried out using benzaldehyde and their derivatives with nitromethane and their derivatives. The Henry products (1-15) were obtained in a very good yield using MgAl-HT-RH catalyst either by conventional method at 90^oC in liquid phase, or under microwave irradiation method. The mesoporous structure and basic nature of re-hydrated solid catalyst were responsible for their superior catalytic efficiency. The robust nature was determined by using the same catalyst for five times, where the product % yield was almost unchanged significantly.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Soil amendments with composted organic materials are recommended to increase soil organic matter (SOM), promote soil fertility, and the Circular Economy. Growing areas of hedged olive groves in southern Iberia peninsula generate huge amounts of olive leaves whose potential as soil organic amendment is not fully studied. An experimental field trial in a hedged olive grove (cv. “Cobrançosa”) was set up near Portalegre, Portugal, to test a compost of olive leaves plus sheep manure (2:1) applied in the row, at soil surface. Three nominal rates (0 or control, 2.5 and 5.0 kg m-2) were used, in a complete randomized block setup (3 treatments, 3 replicas, 9 plots) and soil chemical properties of layers 0-5, 5-15, and 15-30 cm deep were annually monitored. Results (mainly in layer 0-5 cm) showed increases in total N, carbon of the particulate organic matter (POM-C), permanganate oxidizable carbon (POX-C), extractable phosphorus, and zinc, after one year, and increases in soil organic carbon (SOC), C-stock, pHKCl, extractable phosphorus, and zinc, after two years. POX-C was the most sensitive SOM-related indicator, showing increases up to 30 cm deep after one year. This compost improved soil fertility, but should be monitored over longer periods of time, namely for SOC and extractable zinc content.

A recent review of global vitamin C status indicated a high prevalence of deficiency, particularly in low- and middle-income countries, as well as in specific subgroups within high-income countries. Here we provide a narrative of potential factors influencing vitamin C status. The in vivo status of vitamin C is primarily affected by dietary intake and supplement use. Dietary intake can be influenced by cultural aspects such as staple foods and traditional cooking practices. Environmental factors can also affect vitamin C intake and status; these include geographic region, season and climate, as well as pollution. Demographic factors such as sex, age, and race are known to affect vitamin C status, as do socioeconomic factors such as deprivation, education and social class, and institutionalization. Various health aspects affect vitamin C status; these include body weight, pregnancy and lactation, genetic variants, smoking, and disease states, including severe infections as well as various non-communicable diseases such as cardiovascular disease and cancer. Some of these factors have changed over time, therefore we also explore if vitamin C status has shown temporal changes. Overall, there are numerous factors that can affect vitamin C status to different extents in various regions of the world. Many of these factors are not taken into consideration during the setting of global recommended dietary intakes for vitamin C.

The partial discharge (PD) event in high voltage insulation releases energy, exerts mechanical pressure, and generates elastic waves. Detecting and locating these PD events through short-duration acoustic pulses is well-established, particularly in gas-insulated systems and oil-insulated transformers. However, its full potential remains untapped in solid insulation systems, where the propagation capability of acoustic pulse and the acoustic reflections pose fundamental challenges to the Acoustic Emission (AE) detection technique. This study investigates the influence of reflections and multiple paths on the propagating acoustic pulse in polymeric insulating materials using a finite element method (FEM) in COMSOL. It was observed that the reflections from the boundary influence the propagating pulse's shape, peak magnitude, and arrival time. An analytical MATLAB model further quantifies the impact of multiple propagation paths on the shape, magnitude, and arrival time of the pulse travelling in a cylinder. Additionally, a Perfect Matched Layer (PML) was implemented in the COMSOL model to eliminate reflections from the boundary, and it revealed that the acoustic pulse magnitude decreases with distance following the inverse square law. In essence, the models aid in measuring how reflections contribute to the observed signals, facilitating the precise identification of the source of the PD event in the tested system.

Locally Advanced Breast Cancer (LABC) is a complex disease that requires a multidisciplinary approach. Neoadjuvant Chemotherapy (NAC) is usually performed in order to achieve loco-regional radical resection; although its importance in the multidisciplinary approach to LABC is well recognised, a small number of patients show Progressive Disease (PD). No standard Salvage Treatment (ST) has been defined and different strategies can be adopted, such as second line systemic therapies, radiation therapy, and surgery. Herein a case of LABC in PD during NAC is reported with a literature review, with the aim of highlighting the importance of a tailored multidisciplinary treatment in each patient.

: Immune checkpoint inhibitors (ICI) cemiplimab and pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate the effectiveness and safety of ICI in a real-world cSCC population, including patients with conditions which would exclude clinical trial participation. In this single-center, retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We evaluated investigator-assessed best overall response (BOR) and immune-related adverse events (irAEs). We correlated survival outcomes with age, performance status, immune status and irAEs. For the 36 patients identified, best overall response (BOR) to ICI was partial response (PR) in 41.7%, complete response (CR) in 27.8%, and stable disease in (SD) 13.9% of patients. The PFS rate at 1 year was 63%; median PFS was not reached (NR). The median OS was 38.6 months (95% CI 25.4-NR). Immune compromised patients, ECOG performance 2-3, and age ≥75 years were not significantly associated with PFS or OS. IrAE grade 3-4 were seen in 13.9% of patients. In our Canadian experience with real-world patients, ICI was an effective and safe treatment for advanced cSCC patients. Patients achieved great benefit with ICI regardless of age, immune status or ECOG performance status.

Cutaneous T cell lymphomas (CTCLs) are caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies, while some entities, or in advanced stages of disease, have aggressive progression and poor survival. To efficiently treat CTCL consistent entity markers are needed to prevent the delay in diagnosis and to provide disease specific treatment to patients. Recently, the introduction of high throughput parallel sequencing methods resulted in identification of numerous genetic and ep-igenetic alterations affecting the transcriptome of CTCL cells. In this review, most relevant genes, including TOX, CADM1, PLS3, DNM3, CXCL13, PD-1, BCL11B and TMEM244 are reported that are specifically expressed in CTCL. Upon verification their specificity and sensitivity in larger studies, their altered expression will be able to be recognized as novel biomarkers, that can im-prove the early diagnosis of CTCL.

Renewable methanol, obtained from CO₂ and hydrogen provided from renewable energy, has been proposed as a way to close the CO₂ loop. In industry, methanol synthesis using the catalyst CuO/ZnO/Al₂O₃ occurs at a high pressure. We intend to make certain modification on the traditional catalyst in order to work at lower pressure, maintaining high selectivity. Therefore, three heterogeneous catalysts have been synthesized by co-precipitation in order to improve the activity and the selectivity to methanol under mild conditions of temperature and pressure. Certain modifications on the traditional catalyst Cu/Zn/Al₂O₃ were employed such as the modification of the synthesis time and the addition of Pd as a dopant agent. The most efficient catalyst among those tested was a palladium-doped catalyst, 5% Pd/Cu/Zn/Al₂O₃. This had a selectivity of 64% at 210C and 5 bar.

The improvement of the methane combustion activity was observed in cyclic temperature-programmed and isothermal reactions over Pd/ZrO2 catalysts by simple reduction/re-oxidation treatment. The catalytic activity increased during the initial stages of isothermal reaction, and the light-off temperature was lowered as the number of cycles increased in the cyclic temperature-programmed reaction. To reveal the origin of activation, variations in the reduction properties after the activation period were carefully investigated through CH4 temperature-programmed reduction (TPR) measurements. From the CH4-TPR results, it was confirmed that the reduction temperature decreased significantly after activation. The observation of the CH4-TPR peak at relatively low temperatures is directly proportional to the catalytic activity of CH4 combustion. It was therefore concluded that repeated reduction/re-oxidation occurred in the reactant stream, and this phenomenon allowed the combustion reaction to proceed more easily at lower temperatures.

Hydrogen peroxide is an important chemical of increasing demand in today’s world. Currently, the anthraquinone autoxidation process dominates the industrial production of hydrogen peroxide. Herein, hydrogen and oxygen are reacted indirectly in the presence of quinones to yield hydrogen peroxide. Owing to the complexity and multi-step nature of the process, it is advantageous to replace the process with an easier and straightforward one. The direct synthesis of hydrogen peroxide from its constituent reagents is an effective and clean route to achieve this goal. Factors such as water formation due to thermodynamics, explosion risk, and the stability of the hydrogen peroxide produced hinder the applicability of this process at an industrial level. Currently, the catalysis for the direct synthesis reaction is palladium based and the research into finding an effective and active catalyst has been ongoing for more than a century now. Palladium in its pure form, or alloyed with certain metals are some of the new generation of catalysts that are extensively researched. Additionally, to prevent the decomposition of hydrogen peroxide to water, the process is stabilised by adding certain promoters such as mineral acids and halides. A major part of today’s research in this field focusses on the reactor and the mode of operation required for synthesising hydrogen peroxide. The emergence of microreactor technology has helped in setting up this synthesis in a continuous mode, which could possibly replace the anthraquinone process in the near future. This review will focus on the recent findings of the scientific community in terms of reaction engineering, catalyst and reactor design in the direct synthesis of hydrogen peroxide.

Carbon nanotubes (CNTs) are effective supports for nano metals and together they represent hybrids that combine unique properties of both. A microwave induced reaction was used to deposit nano palladium on carboxylated and octadecylamine functionalized multiwall CNTs, which were used to carry out C-C coupling reactions in DMF and toluene. These hybrids showed excellent catalytic activity with yield as high as 99.8% while its enhancement with respect to commercially available Pd/C catalyst reached as high as 109%, and the reactions times were significantly lower. Polarity of the functionalized form was found to be a significant factor with the polar carboxylated CNT showing better activity in DMF while the relatively nonpolar octadecyl amine was better in toluene. The results suggest the possibility of tailor making functionalized CNT when used as catalyst supports

Nowadays, digitalization and automation in both industrial and research activities is a driving force for innovations. In recent years, Machine Learning (ML) techniques - the subset of Artificial Intelligence - have been widely applied as a key tool to automize and digitalize numerous in-dustrial processes. ML models can predict specific features, like materials' lifetime in a heating device, based on recently trained algorithms with applied input data. The results of ML algorithms are easy to interpret and can significantly decrease the time of research and decision-making, thus, substituting the trial-error approach. This work presents the state of the art in the application of Machine Learning in the investigation of MgO-C refractories for the steel industry. Also, the work presents an overview of the most commonly used ML algorithms in refractory engineering. So far published results confirm the high performance of ML, e.g., for prediction of oxidation behaviour, optimum graphite content and wear rate of MgO-C refractories, or for clustering materials based on various fused and sintered MgO sources into groups with similar corrosion resistance, thus, permitting to reduce expensive fused raw materials content. Most of the presented works were positively validated via experiment.

Nonalcoholic fatty liver disease (NAFLD) is a liver metabolism-associated steatohepatitis caused by non-alcoholic factors. NAFLD is currently the most prevalent liver disease in the world, affecting one-fourth of the world's population, and its prevalence increases with age. There are no approved drugs specifically for the treatment of NAFLD, and one important reason hindering drug development is the lack of effective biomarkers. C-reactive protein (CRP), a marker of inflammation, has been linked to NAFLD and aging in recent studies. Coincidentally, hepatocytes are responsible for the major CRP production, and the levels of CRP increase with age. Therefore, CRP is not only a potential marker, but also acts as a key factor driving liver aging and NAFLD. Herein, we reviewed the biological function and production mechanism of CRP and the relationship between CRP and NAFLD. We also comprehensively described the potential molecular mechanisms of CRP-mediated signaling in aging-associated NAFLD. Finally, we proposed possible therapeutic approaches based on the mechanism of CRP signaling in the pathogenesis of NAFLD. We hope this study can provide new insights into the development of aging associated NAFLD biomarkers and suggest that modulation of CRP signaling is a potential therapeutic target.

Consider a uniquely ergodic $C^*$-dynamical system ba\-sed on a unital $*$-endomorphism $\Phi$ of a $C^*$-algebra. We prove the uniform convergence of Cesaro averages $\frac1{n}\sum_{k=0}^{n-1}\lambda^{-n}\Phi(a)$ for all values $\lambda$ in the unit circle which are not eigenvalues corresponding to "measurable non continuous" eigenfunctions. This result generalises the analogous one in commutative ergodic theory presented in [19], which turns out to be a combination of the Wiener-Wintner Theorem (cf. [22]) and the uniformly convergent ergodic theorem of Krylov and Bogolioubov (cf. [15]).

We cultured Parmelina carporrhizans and P. quercina in Corn Meal Agar and 0.2% glucose Malt Yeast Agar for 160 days. Chemosyndrome of natural thalli and mycobiont cultures were analyzed by HPLC. Lecanoric acid, atranorin, chloratranorin and ergosterol were detected in P. carporrhizans thalli, while lecanoric acid, chloratranorin and aliphates were found in P. quercina thalli. The secondary methabolites pattern between thalli and mycobiont culture was completely different in both species. Both species secreted the phenalenone myeloconone C in culture media and was also detected in P. quercina mycobiont aggregates. Interestingly, the phenolic compounds produced by the mycobiont culture of P. carporrhizans are related to those produced by natural thallus by the same biosynthetic pathway, while the chemosyndrome of P. quercina mycobiont implies switch of biosynthetic pathway from acetate-polymalonate pathway to shikimic acid pathway, with pulvinic acid as major compound of mycobiont culture. The role of Myelochonone C, confluentic acid and pulvinic acid produced by mycobiont culture is discussed as possible adaptive vantage in field as photoprotective agent or as byproduct result of stressing artificial culture conditions.

Two series of novel [1,2,4]triazolo[4,3-c]- and [1,2,4]triazolo[1,5-c]quinazoline fluorophores with 4’-amino[1,1′]-biphenyl residue at position 5 have been prepared via Pd-catalyzed cross-coupling Suzuki-Miyaura reactions. The treatment of 2-(4-bromophenyl)-4-hydrazinoquinazoline with orthoesters in solvent-free conditions or in absolute ethanol leads to the formation of [4,3-c]-annulated triazoloquinazolines, whereas [1,5-c] isomers are formed in acidic media as a result of Dimroth rearrangement. 1D-NMR and 2D-NMR spectroscopy as well as single‐crystal X‐ray diffraction analysis unambiguously confirmed the annelation type and determined the molecular structure of p-bromophenyl intermediates and target products. Photophysical properties of the target compounds were investigated in two solvents and solid state and compared with those of related 3-aryl-substituted [1,2,4]triazolo[4,3-c]quinazolines. The excluding of aryl fragment from triazole ring has been revealed to improve fluorescence quantum yield in solution. Most of the synthesized structures show moderate to high quantum yields in solution. Additionally, the effect of solvent polarity on the absorption and emission spectra of fluorophores has been studied and considerable fluorosolvatochromism was stated. Moreover, electrochemical investigation and DFT calculations have been performed, their results are consistent with the experimental observation.

Bermudagrass (Cynodon spp.) is one of the drought-resistant warm-season turfgrasses adapted to the southern and transitional zones in the United States. Multiple hybrid varieties have been developed and released for use as a turfgrass and others are in pipeline. Increasing genetic di-versity of commercial varieties is vital to tackle stress tolerance. A DNA profiling study of 21 experimental selections from the Oklahoma State University (OSU) turfgrass breeding program and 11 cultivars was conducted using 51 simple sequence repeat (SSR) primer pairs that spread across the bermudagrass genome. Pairwise genetic relationship analysis among the genotypes using 352 polymorphic bands showed genetic similarity coefficients ranging from 0.59 to 0.89. Cluster analysis using the un-weighted paired group method with arithmetic average (UPGMA) method grouped the entries into six clusters. Correlation analysis identified different levels of pairwise genetic relationship among the entries that largely reflected parental relationship. Di-rectional breeding and selection for cold hardiness or drought resistance created progeny that had distinct genetic diversity in the tested bermudagrasses. It is evident that an increase in genetic diversity of the existing cultivar pool with the release of one or more of the experimental selec-tions for commercial use will strengthen and improve bermudagrass systems.

We recently formulated Modular Dvoretzky, Type-Cotype, Khinchin-Kahane and Grothendieck Inequality problems in the Appendix of \textit{[arXiv:2302.03718v1]}. For the sake of wide accessibility we give a separate treatment of them.

Vitamin C is an essential nutrient that must be obtained through the diet in adequate amounts to prevent hypovitaminosis C and the potentially fatal deficiency disease scurvy. Global vitamin C status and prevalence of deficiency has not previously been reported, despite vitamin C’s pleiotropic roles in both non-communicable and communicable disease. This review highlights the global literature on vitamin C status and the prevalence of hypovitaminosis C and deficiency. Related dietary intake is reported if assessed in the studies. We also explore if global vitamin C status has changed over time. Overall, the review illustrates the shortage of high quality epidemiological studies of vitamin C status in many countries, particularly low- and middle-income countries. The available evidence indicates that vitamin C deficiency is common in low- and middle-income countries and not uncommon in high income settings. Further high quality studies are required to confirm these findings, including in the countries not yet represented, and to fully understand associations with a range of disease processes. Our findings suggest a need for interventions to prevent deficiency in a range of at risk groups and regions of the world.

In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on the cytotoxicity of CD8+ effector T cells. Interestingly, TWIST1 expression is associated with high-level PD-L1 in triple negative breast cancers (TNBCs). Overexpression and knockdown of TWIST1 robustly upregulates and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to promote PD-L1 expression, which drives immune escape of breast cancer cells by accelerating the exhaustion of CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or blockade of PD-L1 with a PD-L1 antibody significantly enhances CD8+ T cells to inhibit breast cancer cell growth. These results demonstrate that TWIST1 directly induces PD-L1 expression in breast cancer cells to drive immune evasion. Targeting TWIST1, BRD8 or PD-L1 in TNBC should facilitate CD8+ T cell-mediated immune therapy. TWIST1 may also serve as a biomarker for anti-PD-L1 immunotherapy.

Some studies show that patients with mutations in the SNCA gene, which codifies for the alpha-synuclein protein, show a particular phenotype. The effects of SNCA Single Nucleotide Polymorphism (SNPs) in recently diagnosed, drug-naïve patients with PD have been less explored. Therefore, we set out to explore the differences in the clinical characteristics of recently diagnosed drug-naïve sporadic PD patients with or without SNCA rs3910105 or rs356181 SNPs. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data, dementia, psychiatric conditions, a diagnosis change over the first five years from the initial PD diagnosis, or with a familial history of PD. Subjects were evaluated with the MDS-Unified PD Rating Scale (MDS-UPDRS), DAT imaging, the Geriatric Depression Scale (GDS), the State-Trait Anxiety Inventory (STAI), the Montreal Cognitive Assessment (MoCA), the SCOPA-AUT for autonomic function, the Epworth Sleepiness Scale (ESS), the RBD Questionnaire, and the University of Pennsylvania Smell Identification Test (UPSIT). We included 308 PD patients fulfilling all inclusion and exclusion criteria. A logistic regression analysis and Machine-Learning models did not disclose any difference between patients either with or without the SNCA rs3910105 SNP or with or without the SNCA rs3910105 polymorphism. Our results suggest that the SNCA polymorphisms rs3910105 and rs356181 have no impact on the phenotype of idiopathic, sporadic, recently diagnosed, drug naïve PD patients.

Apoptosis under severe hypoxia is induced through p53 phosphorylation and HIF-1α-dependent p53 accumulation via ATR activation by DNA damage response (DDR) activation through replication stress. We previously demonstrated that the topoisomerase I catalytic inhibitor, 3EZ, 20Ac-ingenol, specifically induced apoptosis in Jeko-1 and Panc-1 cells, both of which are cell lines that show cyclin D1 overexpression. After progression to the S phase facilitated by nuclear cyclin D1, in the presence of 3EZ, 20Ac-ingenol, an intra S phase checkpoint was induced in ATR activation as part of replication stress-induced DDR. In this study, we examined whether 3EE, 20Ac-ingenol induces a higher degree of p53 phosphorylation and additional HIF-1α and p53 accumulation in response to replication stress-induced DDR activation under the hypoxic condition than under the normoxic condition by controlling ATR activation. 3EE, 20Ac-ingenol induced p53 activation and HIF-1α-dependent p53 accumulation through cooperative ATR activation via induced DDR with the hypoxia in Panc-1 cells. The Jeko-1 cells showed slight HIF-1α accumulation under hypoxia, but this was not decreased by 3EE, 20Ac-ingenol, so that the cells remained resistant to hypoxia. 3EE, 20Ac-ingenol induces an intricate interplay between p53 and HIF-1α accumulation via ATR activations that results in high p53 accumulation, which advanced transient expression and early disappearance of HIF-1?. The strong p53 accumulation and consequent PTEN activation also decreased HIF-1α accumulation and PD-L1 expression, which resulted in intense apoptosis.

Logic gates made of pairs of NPN and PNP bipolar transistors, similar to CMOS logic gates, have been proposed and patented long ago but did not find any practical application until now. Other bipolar technologies (TTL, TTL-S, ECL), once the technologies of choice for digital systems, were abandoned and superseded by CMOS. In this paper it is shown that now, when truly com-plementary pairs of bipolar transistors can be made, properly biased bipolar gates similar to CMOS gates are feasible, can be thermally stable and find practical applications.

In this paper, we first report that WO_x contained nanoalloys exhibit stable electrocatalytic performance in alkaline media, though bulk WO₃ are easy to be dissolved in NaOH solutions. Carbon supported oxide-rich Pd-W alloy nanoparticles (PdW/C) with different Pd:W atom ratios were prepared by reduction-oxidation method. Among the catalysts, the oxide-rich Pd0.8W0.2/C (Pd/W = 8:2, atom ratio) exhibits the highest catalytic activity for oxygen reduction reaction. The X-ray photoelectron spectroscopy data shows that ~40% of Pd atoms and ~60% of the W atoms are in their oxides form. The Pd 3d_5/2 peaks in oxide-rich Pd-W nanoalloys are positive shift compared with that of Pd/C, which indicates the electronic structure of Pd is affected by the strong interaction between Pd and W/WO₃. Compare to Pd/C, the onset potential of oxygen reduction reaction at the oxide-rich Pd_0.8W_0.2/C is positive shifted. The current density (mA·mg Pd⁻¹) at the oxide-rich Pd_0.8W_0.2/C is ~1.6 times of that at Pd/C. The oxide-rich Pd_0.8W_0.2/C also exhibits higher catalytic stability than Pd/C, which demonstrate that it is a prospective candidate for the cathode of fuel cells operated with alkaline electrolyte.

With the rise of long-read sequencers and long-range technologies, delivering high-quality plant genome assemblies is no longer reserved to large consortia. Indeed, sequencing techniques but also computer algorithms have reached a point where the reconstruction of assemblies at the chromosome-scale is now feasible at the laboratory scale. Current technologies, and especially long-range technologies, are numerous and selecting the most promising one for the genome of interest is crucial to obtain optimal results. In this study, we resequenced the genome of the yellow sarson, Brassica rapa cv. Z1, using the Oxford Nanopore PromethION sequencer and assembled the sequenced data using current assemblers. To reconstruct complete chromosomes, we used and compared three long-range techniques, optical mapping, Omni-C and Pore-C sequencing libraries commercialized by Bionano Genomics, Dovetail Genomics and Oxford Nanopore Technologies respectively, or a combination of the three, in order to evaluate the capability of each technology.

In fuel-cell technological development, one of the most important objectives is to minimize the amount of Pt, the most employed material as oxygen reduction and methanol oxidation electro-catalyst. In this paper we report the synthesis and characterization of Te nanotubes (TeNTs) decorated with Pt nanoparticles, readily prepared from stirred aqueous solutions of PtCl2 containing a suspension of TeNTs and ethanol acting as a reducing agent, avoiding the use of any hydrophobic surfactants as capping stabilizing substance. The as obtained TeNTs decorated with Pt nanoparticles (TeNTs/PtNPs) have been fully characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area diffraction patterns (SAD), X-ray photoelectron spectroscopy (XPS) and cyclic voltammetry (CV). We demonstrate that the new material can be successfully employed in fuel cell either as anodic (for methanol oxidation reaction) and cathodic (for oxygen reduction reaction) electrode with high efficiency in terms of related mass activities and on-set improvement. Remarkably, the cell operates in aqueous electrolyte buffered at pH 7.0, thus avoiding acidic or alkaline conditions that may lead e. g. to Pt dissolution (at low pH) and paving the way for the development of biocompatible devices and on chip fuel cells.

In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients’ mental status, before and 12 weeks after DAA therapy, by assessment scales and psychometric instruments. We subdivided patients into two groups, CHC patients with (Group A) or without (Group B) a current and/or past psychiatric history. After DAA treatment, Group A patients showed low anxiety and improved depression, no variation in self-report distress, but worse general health perceptions. No significant difference emerged from coping strategies. Depression and anxiety improved in Group B, and no change emerged from total self-reported distress, except for somatization. Moreover, Group B increased problem-focused strategies for suppression of competing activities, and decreased strategies of instrumental social support. Contrarily, Group B reduced significantly emotion-focused strategies, such as acceptance and mental disengagement, and improved vitality, physical and social role functioning. DAA therapy is safe and free of hepatological and psychiatric side effects in CHC patients, regardless of current and/or past psychiatric history. In particular, patients without a psychiatric history also remarkably improved their quality of life.

In this work, the use of graphite-like carbon nitride (g-C3N4) with improved texture characteristics for the synthesis of supported palladium catalysts of dehydrogenation of nitrogen-containing heterocycles was studied. This process is key to the creation of liquid organic carrier technology (LOHC) using N-heterocycles as reversibly hydrogenated/dehydrogenated substrates. For the preparation of g-C3N4-mca supports with advanced textural characteristics, well-established technology of the melamine cyanurate complex carbonization and standard techniques of adsorption precipitation together with wet impregnation were used for the synthesis of Pd-containing systems. The activity of the synthesized catalysts was studied in decahydroquinoline dehydrogenation. The high weight content of extractable hydrogen (7.2 wt %) and the high extraction rate, respectively, make it possible to consider these substances as the most promising N-heterocyclic compounds for this technology. It was shown that an increase in the specific surface area of g-C3N4 allows for achieving a slightly lower, but comparable fineness of palladium particles for the 1 wt% Pd/MCA-500 sample, compared to the standard 1 wt% Pd/C. In this case, the catalytic activity of 1 wt% Pd/MCA-500 in dehydrogenation of both substrates exceeded the analogous parameter for catalysts supported by nitrogen free supports. This regularity is presumably associated with the electron-donor effect of surface nitrogen, which favorably affects the dehydrogenation rate as well as the stability of catalytic systems.

Patients with Parkinson’s Disease (PD) experience REM sleep behavior disorder (RBD) more frequently than healthy controls. RBD is associated with torpid disease evolution. To test the hypothesis that differential genetic signatures might contribute to the torpid disease evolution in PD patients with RBD. We compared the rate of genetic mutations in PD patients with or without probable RBD. Patients with a clinical diagnosis of PD in the Parkinson’s Progression Markers Initiative (PPMI) database entered the study. We excluded those with missing data or a diagnosis change over the first five years from the initial PD diagnosis. Probable RBD (pRBD) was confirmed by a REM Sleep Behavior Disorder Screening Questionnaire score &gt;5 points. Logistic regression and Machine Learning (ML) algorithms were used to relate Single Nucleotide Polymorphism (SNPs) in PD-related genes with pRBD. We included 330 PD patients fulfilling all inclusion and exclusion criteria. The final logistic multivariate model revealed that the following SNPs increased the risk of pRBD: GBA_N370S_rs76763715 (OR, 95% CI: 3.38, 1.45-7.93), SNCA_A53T_rs104893877 (8.21, 2.26-36.34), ANK2. CAMK2D_rs78738012 (2.12, 1.08-4.10), and ZNF184_rs9468199 (1.89, 1.08-3.33). Conversely, SNP COQ7. SYT17_rs11343 reduced pRBD risk (0.36, 0.15-0.78). The ML algorithms led to similar results. The predictive models were highly specific (95-99%) but lacked sensitivity (9-39%). We found a distinctive genetic signature for pRBD in PD. The high specificity and low sensitivity of the predictive models suggest that genetic mutations are necessary but not sufficient to develop RBD in PD. Additional investigations are needed.

Tissue programmed death ligand-1 (PD-L1) protein expression is predictive of immune checkpoint inhibitor (ICI) benefit. However, tissue PD-L1 can be fraught with tissue acquisition and heterogeneity limitations. Plasma testing can overcome these limitations. However, the overall survival (OS) predictive benefit of plasma PD-L1 assays have not been well characterized. Patients with stage IV non-small cell lung cancer (NSCLC) and plasma cfRNA PD-L1 by PCR expression were identified and assessed for OS. 16 patients treated with front-line ICI-based regimens were assessed and represented a real-world patient population with over half with a performance status of 2 or greater. 10 contemporaneous patients at the same institution treated with chemotherapy alone were also identified and assessed. With a median follow-up of 33 months, median OS was 13 months with a 30% 3-year OS for the ICI treated patients compared to a median OS of 3 months and a 10% 3-year OS for those treated with chemotherapy alone. Comparative log-rank test p-value = 0.014 and a hazard ratio 0.376 (95%-CI 0.134-1.057). Plasma cfRNA PD-L1 was associated with a statistically significant survival benefit from ICI-based treatment compared to chemotherapy in the first line treatment of a real-world patient population of advanced NSCLC.

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically ‘exhausted’ in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.

Nanotechnology sparks discussions and concerns about the impacts of new nanomaterials on health and the environment. It holds importance in various domains due to its unique struc-tures. Carbon dots (C-dots) are versatile nanomaterials with applications in bioimaging, sensing, catalysis, polymers, solar cells, and more. They offer desirable characteristics such as stability, cost-effectiveness, biocompatibility, and high photoluminescent quantum yield. C-dots have the potential to replace expensive fluorophores in solar cells. They are catego-rized as carbon quantum dots, graphene quantum dots, and carbonized polymer dots. C-dots have outstanding optical and photoelectric properties with low toxicity. Bottom-up and top-down approaches are used for the synthesis of carbon dots (CDs), with each method im-pacting their physicochemical characteristics. The choice of synthesis method depends on de-sired properties and application requirements. Researchers combine these methods and ex-plore new approaches to enhance synthesis efficiency and tailor CD properties. CDs have di-verse chemical structures with modified oxygen, polymer-based, or amino groups on their surface. Various characterization methods such as HRTEM, XPS, and optical analysis (PL, UV) are used to determine CD structure. Carbon dots (CDs) are cutting-edge fluorescent nano-materials with remarkable qualities such as biocompatibility, low toxicity, environmental friendliness, high water solubility, and photo-stability. They are easily adjustable in terms of their optical properties, making them highly versatile in various fields. CDs find applications in bio-imaging, nanomedicine, drug delivery, solar cells, LEDs, photo-catalysis, elec-tro-catalysis, and other related areas.

The purpose of the study is to show the effect of the intake of vitamin C obtained from a diet rich in fruit and vegetables or vitamin C supplements on the level of vitamin C in the plasma. The level of vitamin C in plasma were determined before the study (T1), and after five months (T2). Moreover, a medical record was carried out and a questionnaire on the habits such as general eating and specific consumption of food rich in vitamin C. Both of them were completed before and after five months. In addition, related anthropometric analyses were carried out. The results of the first determination of vitamin C level in plasma were between 1.0 and 16.0 mg/L and the results of the second determination of vitamin C in plasma were between 4.9 and 14.1 mg/L. Furthermore, it was identified that 50% of the questioned people had a low fruit intake. Raw vegetables were consumed by fewer people, the intake being higher during the main meals. The correlation of plasma vitamin C with the eating habits of the subjects to the study points out an interdependence between the consumption of fruit and vegetables and the level of vitamin C in the plasma.

Adenoviruses are associated with respiratory tract, gastrointestinal or, less frequently, other involvement. Epidemics of adenovirus infections occur globally, in communities and in closed or crowded settings. In our institution, an outbreak of Adenovirus infection in infants and children was recently observed. Two main patterns of clinical presentation were observed: 68 patients had mainly respiratory symptoms (pharyngitis n=67, cough n=44; tonsillar exudate n=17; other respiratory signs n=4) while 26 patients showed prevalent gastrointestinal involvement (diarrhea n=26, vomiting n=8). Patients with respiratory symptoms had a significantly higher count of WBC, PMN and platelets, while CRP level approached statistical significance (p=0.07) for higher values in the patients with diarrhea. In order to explore the impact of selected presenting features, possible association between level of CRP and presence of pharyngeal exudate, cough, vomiting, diarrhea, duration of fever, number of neutrophils, and administration of antibiotics was analyzed. Patients falling in the tertile with more elevated CRP values had significantly more often tonsillar exudate and diarrhea, while those in the lower tertile had a 4.4 days duration of fever, vs. ≥5.0 days in the remaining patients. Antibiotic therapy was administered more frequently to patients with higher values of CRP (p=0.006). Duration of hospitalization was not associated with the CRP level. The median time from the receipt of positive adenovirus PCR test result to patient discharge was 1 day in 73% of cases. The number of copies of adenovirus detected by PCR ranged between 47 million and 15/L. Falling in the highest terzile of copy number was significantly associated with pharyngitis. The 24 patients with evidence of viral coinfection had no difference in the demographics or presenting features, with the only exception of a significantly higher leukocyte count. Rapid turn-around of results of molecular testing of adenovirus genome on pharyngeal swab allowed us to rapidly diagnose adenovirus infection, allowing stopping antibiotic therapy and immediate discharge, with reduced discomfort for the families and more appropriate use of hospital beds. A high copy number of adenovirus from pharyngeal swab should not be taken as an indicator of worse prognosis, thus allowing preferential use of qualitative rather than quantitaive assay.

Aging is a complex process associated with tissue degeneration and an increased risk of age-related diseases. This study aimed to evaluate the impact of Terasen®, a nutraceutical containing standardized extracts of Euterpe oleracea, Myrciaria dubia, and purified oil of Bixa orellana and Astrocaryum aculeatum on the lifespan of Caenorhabditis elegans, a widely used model organism for aging research. The findings demonstrated that Terasen® exhibited significant antioxidant activity and influenced the feeding behavior of C. elegans, leading to a reduced pharyngeal pumping rate and a decreased number of offspring produced by treated individuals. Notably, Terasen® also displayed a remarkable ability to extend the lifespan of C. elegans. These findings suggest that Terasen® may possess promising anti-aging effects in vivo, warranting further investigation.

The involvement of NK and other cytotoxic cells is considered the first defense' line against cancer. However, a significant lack of information prevails on the possible roles played by factors considered characteristic of primitive cells, such as c-kit and Sca-1, in activating these cells, particularly in melanoma models subjected to treatments with substances under investigation, such as the case of norcantharidin. In this study, B16F1 murine melanoma cells were used to induce tumors in DBA/2 mice, estimating the proportions of NK and iNKT cells, the presence of activation (CD107a+) and primitive/activation (c-kit+/Lya6A+) markers, some tumor parameters, such as the presence of mitotic bodies, nuclear factor area, NK and iNKT cell infiltration in the tumor, infiltrated tumor area, and infiltrating lymphocyte count at 10x and 40x in specimens treated with pentoxifylline, norcantharidin and the combination of both drugs. Possible correlations were estimated with Pearson's correlation analysis. Despite having demonstrated multiple correlations, it should be noted that immaturity/activation markers were related to these cells' activation. At the tumor site, iNKT cells are the ones that exert the cytotoxic potential on tumor cells, but they are confined to specific sites in the tumor. Due to the higher number of interactions of natural killer cells with tumor cells, it is concluded that the most effective treatment was PTX at 60 mg/kg + NCTD at 0.75 mg/kg.

Modified nucleobases are potentially useful building blocks when containing catalytically active functionalities and could be introduced in chiral tridimensional molecules such as nucleic acids, which creates the premises for the development of novel catalytic species. Herein we describe the synthesis of a novel β-C-nucleoside bearing a diol group at anomeric position, amenable as metal ligand or as organo-catalyst. The abasic ligand was successfully prepared and inserted into complementary DNA strand.

Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in proliferation, inflammation and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal) we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing HCV 4a core protein were more susceptible to the LPS/Dgal model while mice expressing HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis, while linking HCV core protein genetic variability to differential pathology in vivo.

Abstract: Carbohydrates form the major source of energy in Asian diets. A lower carbohydrate diet became the recommended golden standard for healthy lifestyle. However, the effects of low-carbohydrates diet on health in apparently healthy individuals have been poorly studied, especially in relation to insulin resistance syndrome (IRS). A total of 120 healthy weight participants with no previous history of a major medical condition and an average BMI of ≤ 25kg/m2 were recruited. Self-reported dietary intake and objective physical activity by accelerometry were tracked for seven days. Participants were divided into three categories according to their dietary intake of carbohydrates. Blood samples were collected for metabolic markers analysis. HOMA of insulin resistance (HOMA-IR), β-cell function (HOMA-B) and C-peptide were used to evaluate glucose homeostasis. The consumption of low carbohydrates (less than 45% of total energy) significantly correlated with higher HOMA-IR, Lower HOMA-β % compared to moderate carbohydrate intake (between 45% to 65%). However, only the HOMA-β % was significantly influenced by carbohydrates intake. Moreover, low carbohydrates intake was significantly associated with elevated C-peptide secretion. The substitution of carbohydrates with other macronutrients, such as fat and proteins in the Atkins/ketogenic diet, resulted in a pronounced induction of IRS-related inflammatory markers; FGF2, IP-10, IL-6, IL-17A, MDC and reduction of IL-13. Overall, the presented data highlight, for the first time, that low carbohydrate intake results in significant glucose homeostasis imbalance that may be driven by a heightened state of inflammatory response.

Vitamin C is important in preventing and slowing the progression of many diseases. There is significant evidence linking periodontal disease and vitamin C. We aimed to systematically review studies addressing the relationship between vitamin C and periodontal disease and the preventive ability of vitamin C against periodontal disease. Electric searches were performed using PubMed, EMBASE, Cochrane Library, and Web of Science. Studies addressing the relationships between periodontal disease and vitamin C in adults aged over 18 years were included. Quality assessment was done using Critical Appraisal Skills Program guideline and GRADE-CERQual. Seventy hundred and sixteen articles were retrieved and fifteen articles (7 cross-sectional studies, 2 case-control studies, 2 cohort studies, and 4 randomized controlled trial [RCT]) were selected by reviewing all articles. Vitamin C intake and blood level were negatively related to periodontal disease in all 7 cross-sectional studies. Subjects who suffer from periodontitis presented lower vitamin C intake and lower blood vitamin C level than subjects without periodontal disease in the two case-control studies. Patients with lower dietary intake or lower blood level of vitamin C showed greater progression of periodontal disease than did the controls. Intervention using vitamin C administration improved gingival bleeding in gingivitis but not in periodontitis. Alveolar bone absorption was also not improved. The present systematic review suggested that vitamin C contributes to reduced risk of periodontal disease.