Additional Methyl Research Articles

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations.

We present a new class of tunable aryl alkyl ionic liquids (TAAILs) based on 1-aryl-4,5-dimethylimidazolium cations with electron-withdrawing and -donating substituents in different positions of the phenyl ring and the bis(trifluoromethylsulfonyl)imide (NTf2) anion. We investigated the effect of additional methyl groups in the backbone of the imidazolium core on the physical properties regarding viscosity, conductivity and electrochemical window. With an electrochemical window of up to 6.3 V, which is unprecedented for TAAILs with an NTf2 anion, this new class of TAAILs demonstrates the opportunities that arise from modifications in the backbone of the imidazolium cation.

Non-monotonic lattice expansion in zeolitic imidazolate frameworks during heating.

The effect of substituting linkers with two additional methyl groups for conventional benzimidazolate on the thermal expansion behaviour of ZIF-62 was investigated by high-energy in situ X-ray diffraction. Increased structural integrity was observed with the addition of methyl groups, and variable anisotropic thermal expansion was discovered in ZIF-62 and its derivative.

Exploring Cinnamoyl-Substituted Mannopyranosides: Synthesis, Evaluation of Antimicrobial Properties, and Molecular Docking Studies Targeting H5N1 Influenza A Virus.

The pursuit of innovative combinations for the development of novel antimicrobial and antiviral medications has garnered worldwide interest among scientists in recent times. Monosaccharides and their glycosides, such as methyl α-d-mannopyranoside derivatives, play a significant role in the potential treatment of viral respiratory pathologies. This study was undertaken to investigate and assess the synthesis and spectral characterization of methyl α-d-mannopyranoside derivatives 2-6, incorporating various aliphatic and aromatic groups. The investigation encompassed comprehensive in vitro antimicrobial screening, examination of physicochemical properties, molecular docking analysis, molecular dynamics simulations, and pharmacokinetic predictions. A unimolar one-step cinnamoylation reaction was employed under controlled conditions to produce methyl 6-O-cinnamoyl-α-d-mannopyranoside 2, demonstrating selectivity at the C-6 position. This represented a pivotal step in the development of potential antimicrobial derivatives based on methyl α-d-mannopyranoside. Subsequently, four additional methyl 6-O-cinnamoyl-α-d-mannopyranoside derivatives were synthesized with reasonably high yields. The chemical structures of these novel analogs were confirmed through a thorough analysis of their physicochemical properties, elemental composition, and spectroscopic data. In vitro antimicrobial assays were conducted against six bacterial strains and two fungal strains, revealing promising antifungal properties of these methyl α-d-mannopyranoside derivatives in comparison to their antibacterial activity. Moreover, cytotoxicity testing revealed that the compounds are less toxic. Further supporting these findings, molecular docking studies were performed against the H5N1 influenza A virus, indicating significant binding affinities and nonbonding interactions with the target protein 6VMZ. Notably, compounds 4 (-7.2) and 6 (-7.0) exhibited the highest binding affinities. Additionally, a 100 ns molecular dynamics simulation was conducted to assess the stability of the complex formed between the receptor 6VMZ and methyl α-d-mannopyranoside derivatives under in silico physiological conditions. The results revealed a stable conformation and binding pattern within the stimulating environment. In silico pharmacokinetic and toxicity assessments of the synthesized molecules were performed using Osiris software (version 2.9.1). Compounds 4 and 6 demonstrated favorable computational and pharmacological activities, albeit with a low drug score, possibly attributed to their higher molecular weight and irritancy. In conclusion, this study showcases the synthesis and evaluation of methyl α-d-mannopyranoside derivatives as promising candidates for antimicrobial and antifungal agents. Molecular docking and dynamics simulations, along with pharmacological predictions, contribute to our understanding of their potential therapeutic utility, although further research may be warranted to address certain pharmacological aspects.

Exploring the role of brain DNA methylomic signatures on gene expression dynamics of frontotemporal lobar degeneration

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, which includes frontotemporal dementia and progressive supranuclear palsy. About 90% of the FTLD cases show either TDP‐43 or tau pathology (FTLD‐TDP or FTLD‐tau, respectively). Though aberrant brain DNA methylation has consistently been associated with Alzheimer’s disease and other neurodegenerative diseases, studies on FTLD are scarce. The main goal of this study was to investigate DNA methylation variation in FTLD bulk brain tissue and brain‐derived nuclei.MethodsWe used bulk frontal cortex genome‐wide DNA methylation profiles (Illumina 450K or EPIC microarrays) from three FTLD cohorts (N = 228). To identify unique and shared differentially methylated loci across FTLD subgroups/subtypes, we performed cohort‐specific epigenome‐wide association studies (EWAS) followed by a meta‐analysis. Additionally, we used weighted gene correlation network analysis to identify co‐methylation signatures associated with FTLD, FTLD pathological subtypes, and other disease‐related traits. To identify disturbed cell‐types and biological processes within disease associated signatures, we then carried out cell‐type and functional enrichment analyses. We also generated and have ongoing analysis of DNA methylation profiles (EPIC microarrays) of neuronal (NeuN+) and glial nuclei (NeuN‐) from FTLD‐TDP cases and controls (N = 40). Wherever possible, we also integrated additional DNA methylation, and gene and protein expression datasets.ResultsIn bulk tissue, the EWAS meta‐analysis identified four shared differentially methylated loci in FTLD, including hypomethylation in OTUD4, a gene we found to be upregulated (mRNA and protein) in FTLD. Two of the four meta‐analysis hits (mapping to OTUD4 and CEBPZ), were found to be co‐methylated within signatures strongly associated with FTLD. Disease‐associated signatures implicate transcription regulation, the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling, and specific brain cell‐types, including pyramidal neurons and oligodendrocytes, in FTLD. Preliminary analysis of the neuronal and glial datasets also revealed FTLD‐associated DNA methylation signatures, which will further inform on cell‐type‐specific changes in FTLD.ConclusionsOur findings identified novel FTLD‐associated loci, including OTUD4, and point to DNA methylation as an important mechanism in the dysregulation of biological processes relevant to the FTLD pathogenesis, such as RNA/stress granule formation.

Effect of Additive Methyl Nicotinate on Electrochemical Behavior of Nickel–Copper Alloy Electrodeposition in ChCl-EG Deep Eutectic Solvents

Effect of Additive Methyl Nicotinate on Electrochemical Behavior of Nickel–Copper Alloy Electrodeposition in ChCl-EG Deep Eutectic Solvents

1,10‐Phenanthroline‐Based Octahedra Induced by Protonation of a Nitrogen Atom: Structures and Emission Properties

AbstractAlthough a few metal‐free octahedral compounds based on nitrogen‐containing ligands are known, the realization of mixed ligand compounds remains difficult. To obtain an improved understanding of this class of compounds, two new octahedral compounds, [(tmphenH)(phen)]PF6, and [(tmphenH)(tmphen)]PF6 (where tmphen=3,4,7,8‐tetramethyl‐1,10‐phenanthroline and phen=1,10‐phenanthroline), were synthesized. The relationship between the emission properties, as evaluated using experimental measurements and theoretical calculations, and structures of the protonated compounds was studied. In addition, differences between the atomic charge distributions and geometries in the ground and singlet excited states were investigated using density functional theory calculations. Both [(tmphenH)(phen)]PF6 and [(tmphenH)(tmphen)]PF6 formed hydrogen‐bonded octahedrons in acetonitrile solution, even in the excited state. However, the hydrogen bonding in [(tmphenH)(phen)]PF6 was weak and thermal vibrations decreased the emission intensity. In contrast, the additional methyl substituents in [(tmphenH)(tmphen)]PF6 suppressed thermal vibrations, resulting in a higher emission intensity.

Inert Group-Containing Electrolyte Additive Enabling Stable Aqueous Zinc-Ion Batteries.

Aqueous zinc ion batteries (AZIBs) are considered promising energy storage devices because of their high theoretical energy density and cost-effectiveness. However, the ongoing side reactions and zinc dendrite growth during cycling limit their practical application. Herein, trisodium methylglycine diacetate (Na3MGDA) additive containing the additional inert group methyl is introduced for Zn anode protection, and the contribution of methyl as an inert group to the Zn anode stability is discussed. Experimental results reveal that the methyl group with various effects enhances the interaction between the polar groups in Na3MGDA and the Zn2+/Zn anode. Thus, the polar carboxylate negative ions in MGDA anions can more easily modify the solvation structure and adsorb on the anode surface in situ to establish a hydrophobic electrical double layer (EDL) layer with steric hindrance effects. Such the EDL layer exhibits a robust selectivity for Zn deposition and a significant inhibition of parasitic reactions. Consequently, the Zn||Zn symmetric battery presents 2375h at 1mAcm-2, 1mAhcm-2, and the Zn||V6O13 full battery provides 91% capacity retention after 1300 cycles at 3Ag-1. This study emphasizes the significant role of inert groups of the additive on the interfacial stability during the plating/stripping of high-performance AZIBs.

Synthesis of lesquerella‐based bisphosphonates

AbstractHydroxy fatty acids (HFAs) have found wide use in today's market, ranging from industrial materials to pharmaceuticals. Castor oil, which is obtained from castor seeds, has served as a primary source of the most common HFA, ricinoleic acid, but also contains several undesirable compounds which pose severe health risks, the most notable being ricin, an unusually stable, toxic protein. A promising HFA alternative is lesquerella oil, an oil obtained from seeds of the Lesquerella fendleri species. Lesquerella oil is mainly comprised of lesquerolic acid, an HFA that is structurally similar to ricinoleic acid, the only difference being that lesquerolic acid possesses two additional methylene groups on the carboxyl end of the molecule. In addition, the bisphosphonate moiety has been shown to display interesting biological activities, primarily as osteoporosis drugs and anti‐cancer therapeutics. The synthesis of lesquerella‐based bisphosphonates, both an unsaturated and saturated series, have been produced in high yields and high purity and are reported here.

Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor

The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.

Elucidating the Effect of Amine Charge State on Poly(β-amino ester) Degradation Using Permanently Charged Analogs.

With synthetic ease and tunable degradation lifetimes, poly(β-amino ester)s (PBAEs) have found use in increasingly diverse applications, from gene therapy to thermosets. Protonatable amines in each repeating unit impart pH-dependent solution behavior and lifetimes, with acidic conditions favoring solubility, yet slowing hydrolysis. Due in part to these interconnected phenomena governing pH-dependent PBAE degradation, predictive degradation models, which would enable user-defined lifetimes, remain elusive. To separate the effects of charge state and solution pH on PBAE degradation, we synthesized poly(β-quaternary ammonium ester)s (PBQAEs), which differ from their parent PBAEs only by an additional methyl group, generating polymers with pH-independent cationic charge. Like PBAEs, PBQAE hydrolysis accelerates with increasing pH, although at a given pH, PBAE degradation outpaces PBQAE degradation. This difference is more pronounced in basic solutions, suggesting that deprotonated PBAE amines accelerate hydrolysis, providing an additional tuning parameter to PBAE lifetime and informing the degradation of PBAEs and other pH-responsive polymers.

Thermal annealing promoted room temperature phosphorescence: motion models and internal mechanism.

Thermal annealing has been proven to be an efficient method to optimize the device performance of organic and polymeric opto-electronic materials. However, no detailed information of aggregate structures was obtained for a deeper understanding of what happens during thermal annealing. Herein, through modulation of molecular configurations by tunable linkage positions, and the amplified amplitudes of molecular motions by incorporation of additional methylene units, accurate changes of aggregated structures upon thermal annealing have been achieved, accompanying with the 'turn-on' room temperature phosphorescence (RTP) response by about 4800- and 177-fold increase of lifetimes. The stretching and swing motion models have been proposed, which afforded an efficient way to investigate the science of dynamic aggregation in depth.

Effect of Additional Variations Hydroxyl Propyl Methyl Cellulose (HPMC) on Making of Patchouli Waxing Gel

Waxing gel is included in cosmetic epilation which can damage the skin barrier. To overcome this, it is necessary to add a composition that can moisturize, prevent irritation, and maximize its lifting power. In minimizing the possibility of irritation, it is necessary to add allantoin to waxing preparations as a calming agent that is safe for sensitive skin. The purpose of this study was to determine the effect of the of Hydroxyl Propyl Methyl Cellulose (HPMC) on the resulting waxing gel preparation including aroma, thickness, and maximum hair lift in certain areas of the body and to determine the best HPMC for removing unwanted hair. This type of research is experimental research with independent variables, namely HPMC variations of 0%, 1%, 2%, 3%, and 4%. The research procedure consists of preparation of tools, preparation of raw materials, and products produced. After that, several panelists made observations by giving questionnaires regarding aroma, viscosity and lifting power. The results showed that there was a comparative effect of the HPMC s used. Based on the observations of several panelists on the aroma, thickness, and lifting power of the waxing gel that has been made, it is known that at the HPMC 0% and 1% HPMC variables, it was found that many panelists stated that the waxing gel in these variables had a fragrant aroma, had a very rich texture. viscous and has very good lifting power compared to waxing gel variables , namely 2% HPMC, 3% HPMC, and 4%.

Repetitive Transcranial Magnetic Stimulation Reduces Depressive-like Behaviors, Modifies Dendritic Plasticity, and Generates Global Epigenetic Changes in the Frontal Cortex and Hippocampus in a Rodent Model of Chronic Stress.

Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.

In vitro cannabinoid receptor activity, metabolism, and detection in seized samples of CH-PIATA, a new indole-3-acetamide synthetic cannabinoid.

The rapidly evolving synthetic cannabinoid receptor agonist (SCRA) market poses significant challenges for forensic scientists. Since the enactment of a generic ban in China, a variety of new compounds have emerged capable of evading the legislation by carrying new structural features. One recent example of a SCRA with new linker and head moieties is CH-PIATA (CH-PIACA, CHX-PIATA, CHX-PIACA). CH-PIATA bears an additional methylene spacer in the linker moiety between the indole core and the traditional carbonyl component of the linker. This study describes detections in 2022 of this new SCRA in the United States, Belgium, and Scottish prisons. CH-PIATA was detected once in a seized powder by Belgian customs and 12 times in Scottish prisons in infused papers or resin. The metabolites of CH-PIATA were investigated via in vitro human liver microsome (HLM) incubations and eight metabolites were identified, dominated by oxidative biotransformations. A blood sample from the United States was confirmed to contain a mixture of SCRAs including CH-PIATA via presence of the parent and at least five of the metabolites identified from HLM incubations. Furthermore, this paper evaluates the intrinsic in vitro cannabinoid 1 and 2 (CB1 and CB2) receptor activation potential of CH-PIATA reference material and the powder seized by Belgian customs by means of β-arrestin 2 recruitment assays. Both the reference and the seized powder showed a weak activity at both CB receptors with signs of antagonism found. Based on these results, the expected harm potential of this newly emerging substance remains limited.

An overview of DNA methylation markers for early detection of gastric cancer: current status, challenges, and prospects.

Background: Gastric cancer (GC) is one of the most common malignancies, with a low 5-year survival rate. However, if diagnosed at an early stage, it can be cured by endoscopic treatment and has a good prognosis. While gastrointestinal X-ray and upper endoscopy are used as national GC screening methods in some GC high-risk countries, such as Japan and Korea, their radiation exposure, invasiveness, and high cost suggest that they are not the optimal tools for early detection of GC in many countries. Therefore, a cost-effective, and highly accurate method for GC early detection is urgently needed in clinical settings. DNA methylation plays a key role in cancer progression and metastasis and has been demonstrated as a promising marker for cancer early detection. Aims and methods: This review provides a comprehensive overview of the current status of DNA methylation markers associated with GC, the assays developed for GC early detection, challenges in methylation marker discovery and application, and the future prospects of utilizing methylation markers for early detection of GC. Through our analysis, we found that the currently reported DNA methylation markers related to GC are mainly in the early discovery stage. Most of them have only been evaluated in tissue samples. The majority of non-invasive assays developed based on blood lack standardized sampling protocols, pre-analytical procedures, and multicenter validation, and they exhibit insufficient sensitivity for early-stage GC detection. Meanwhile, the reported GC DNA methylation markers are generally considered pan-cancer markers. Conclusion: Therefore, future endeavors should focus on identifying additional methylation markers specific to GC and establishing non-invasive diagnostic assays that rely on these markers. These assays should undergo multicenter, large-scale prospective validation in diverse populations.

Reduced Energetic Disorders in Dion–Jacobson Perovskites for Efficient and Spectral Stable Blue LEDs

AbstractMetal halide perovskites have witnessed great success in green, red, and near‐infrared light‐emitting diodes (LEDs), yet blue LEDs still lag behind. Reducing undesired energetic disorders – broad n‐phases and halide segregation – is considered as the most critical strategy to further improve the performances. Here, the study reports a newly designed and synthesized di‐ammonium ligand with rigid π‐conjugated rings and additional methyl groups to construct Dion–Jacobson (DJ) structure. Augmented coordination from the extra ammonium site and increased effective bulkiness from methyl groups lead to better distribution control over conventional mono‐ammonium ligands. This enhances the radiative recombination of blue emissions in the film with homogeneous energy landscape and improved surface morphology, as evidenced by a series of imaging and mapping techniques. As a result, it demonstrates DJ perovskite LEDs (PeLEDs) with peak external quantum efficiencies of ≈4% at 484 nm and ≈11% at 494 nm, which are among the top reported for pure DJ phase‐based PeLEDs in the corresponding wavelength regions. The results deepen the understanding of regulating energetic disorders in perovskite materials via molecular engineering.

An Insight into the Active sites of the RNA Polymerase and Proofreading Exonuclease of the Human Respiratory Syncytial Virus

Human respiratory syncytial virus (hRSV) is one of the triple epidemic viruses that causes infections of the respiratory tract and lungs. For multiplication of the virus in human cells, its RNA polymerase is the crucial enzyme and it forms a part of a large protein (LP). The LP is a multicomponent and multifunctional protein harboring at least 3 different enzymes. The RNA polymerase belongs to RNA-dependent RNA polymerase (RdRp) (EC: 2.7.7.48) type and performs the synthesis of both mRNAs (transcription) and genomic RNA (gRNA) (replication). In addition to the RNA polymerase, the LP also harbours two more enzymes, viz. enzymes for cap addition and cap methylation of mRNAs. The polymerase domain of the LP is analyzed for its active site amino acids and its proofreading (PR) domain. Two polymerase active site regions and a DEDD-superfamily of 3’→5’ PR exonuclease active site domain are identified in the polymerase region. The signature metal-binding motifs, viz. -GDNQ- and –SDD- which are commonly found in the RdRps of all the (-) strand RNA viral pathogens are also found in the hRSV RNA polymerase. The two highly conserved polymerase catalytic core regions identified by sequence similarity are in close agreement with other DNA/RNA polymerases already reported and hence, proposed to function in the nucleotidyl transfer reactions. Presence of the two catalytic regions also suggest that the polymerase may function in a dual mode, one for transcription and the other one for replication, using the same invariant catalytic Mg2+-binding –GDNQ- and –SDD- motifs.

Synthesis and Biological Evaluation of α-Tocopherol Derivatives as Potential Anticancer Agents

α-Tocopheryl succinate (α-TS) and α-tocopheryloxyacetic acid (α-TEA) are potent inducers of apoptosis in cancer cells and efficient suppressors of tumors in experimental model cancer cell lines. They exhibit selective cytotoxicity against tumor cells and very limited or no toxicity toward nonmalignant cells. In the present work, a series of new α-tocopherol derivatives were synthesized as analogs of α-TS and α-TEA. The cytotoxic activity of obtained compounds was tested using three human cancer cell lines, including chronic lymphoblastic leukemia (CEM), breast adenocarcinoma (MCF7), cervical adenocarcinoma (HeLa), and normal human fibroblasts (BJ). The introduction of an alkyl substituent into the ether-linked acetic acid moiety in α-TEA increased anticancer activity. α-Tocopheryloxy-2-methylpropanoic acid with two additional geminal methyl groups was more active against CEM cells compared to α-TEA and non-toxic to normal cells. In order to acquire a deeper understanding of the biological activity of synthesized compounds, a molecular docking study was also conducted. Our research confirmed that vitamin E derivatives are interesting and valuable compounds in terms of their potential therapeutic use as anticancer agents.

High-risk constitutional MLH1 methylation as a cause of early-onset colorectal and endometrial cancers displaying mismatch repair deficiency and MLH1 methylation.

10518 Background: Mismatch repair deficiency (MMRd) occurs in ~15% of colorectal (CRC) and ~30% of endometrial (EC) cancers, of which ~20% are caused by Lynch syndrome (LS). Universal screening of all incident CRC and EC for MMRd uses MLH1 methylation (in tumors with MLH1-loss by immunohistochemistry) to omit common sporadic cases from follow-up germline testing for LS. However, this overlooks unusual cases with constitutional MLH1 methylation (epimutation), a poorly-recognized high-risk mechanism for LS-type cancers that are MLH1 methylated. We aimed to determine the role and prevalence of constitutional MLH1 methylation among CRC and EC cases with tumor MLH1 methylation from clinical and population-based series and if age limits could be used to triage cases warranting additional germline methylation testing. Methods: We screened blood DNA for constitutional MLH1 methylation by pyrosequencing and methylation-specific qPCR in patients with MLH1-loss, MLH1 methylated CRC and EC ascertained from: i) cancer clinics, referred by oncologists and genetic counsellors; ii) Ohio population-based “Columbus” and “OCCPI” cohorts. Bisulfite sequencing confirmed constitutional MLH1 methylation. Results: In clinical cases, constitutional MLH1 methylation was identified in 3/7 EC and 3/8 CRC cases < 60 years. In population-based cohorts, constitutional MLH1 methylation was identified in 4/95 (4.2%) and 4/281 (1.4%) CRC cases of all ages from Columbus and OCCPI, respectively. Highest rates of detection with the majority of cases detected were at age ≤55 years, with 3/4 (75%) in Columbus and 4/17 (23.5%) in OCCPI ≤55 years. For EC, constitutional MLH1 methylation was identified in 0/68 Columbus cases of all ages and 1/24 OCCPI cases < 60 years (age-limited testing). She was one of six (~17%) cases < 50 years in the combined cohorts. EC was the first/dual-first presenting “sentinel” cancer in three female patients with constitutional MLH1 methylation. Of the 14 cases with constitutional MLH1 methylation, nine had hemiallelic methylation (~50% alleles methylated, affecting a single parental allele) and five had mosaicism across various normal tissues. Somatic “second-hits” affecting the unmethylated allele were found in the tumors of mosaic cases, demonstrating causation. Conclusions: A correct diagnosis of constitutional MLH1 methylation at first cancer presentation is important as it will significantly alter clinical management of these high-risk patients. Although rare overall, high rates of detection were found ≤55 years for CRC and ≤50 years for EC cases with a MMRd, MLH1 methylated tumor, entailing minimal extra screening. Testing for constitutional MLH1 methylation is warranted in patients with young-onset CRC or EC, or syn/metachronous cancers at any age, with MMRd and MLH1 methylated tumor(s).

Novel Chlorin e6-Curcumin Derivatives as a Potential Photosensitizer: Synthesis, Characterization, and Anticancer Activity.

Novel series of chlorin e6-curcumin derivatives were designed and synthesized. All the synthesized compounds 16, 17, 18, and 19 were tested for their photodynamic treatment (PDT) efficacy against human pancreatic cancer cell lines: AsPC-1, MIA-PaCa-2, and PANC-1. The cellular uptake study was performed in the aforementioned cell lines using fluorescence-activated cell sorting (FACS). 17, among the synthesized compounds with IC50 values of 0.27, 0.42, and 0.21 µM against AsPC-1, MIA PaCa-2, and PANC-1 cell lines, respectively, demonstrated excellent cellular internalization capability and exhibited higher phototoxicity relative to the parent Ce6. The quantitative analyses using Annexin V-PI staining revealed that the 17-PDT-induced apoptosis was dose-dependent. In pancreatic cell lines, 17 reduced the expression of the anti-apoptotic protein, Bcl-2, and increased the pro-apoptotic protein, cytochrome C, which indicates the activation of intrinsic apoptosis, the primary cause of cancer cell death. Structure-activity relationship studies have shown that the incorporation of additional methyl ester moiety and conjugation to the enone moiety of curcumin enhances cellular uptake and PDT efficacy. Moreover, in vivo PDT testing in melanoma mouse models revealed that 17-PDT greatly reduced tumor growth. Therefore, 17 might be an effective photosensitizer for PDT anticancer therapy.