Introduction

Squamous cell carcinoma (SCC) occurring in the craniofacial region poses significant challenges due to its location and aggressive nature. This study explores the application of Fourier transform infrared spectroscopy (FTIR) as an innovative approach to unravel molecular responses within craniofacial SCC. This technique holds clinical promise for early diagnosis, personalized treatment, intra-operative diagnosis, and preventive screening.

Infrared spectroscopy reveals molecular vibrations, providing unique fingerprints of biological tissues. In craniofacial SCC, FTIR plays a key role in distinguishing cancerous from non-cancerous tissue by identifying characteristic spectral markers. These markers correspond to changes in vibrational modes of biomolecules like lipids, proteins, nucleic acids, and carbohydrates. Notably, alterations in lipid content and protein conformation reflect changes in the tumor microenvironment, cell proliferation, and differentiation.

Aim

The study aims to evaluate the protocol for differentiating SCC tissue from non-SCC tissue based on the infrared spectroscopic response.

Materials and methods

Samples were collected from craniofacial SCC patients at the Department of Cranio-Maxillo-Facial Surgery. FTIR investigations utilized an Agilent Cary 640 spectrometer, with data analyzed through chemometric analysis focusing on 2 and 3 main components.

Results

The study demonstrates a statistically significant separation of cancerous and healthy tissue, varying among patients. Even in cases with subtle differences, speculation arises about the presence of cancerous lesions or tumor markers in healthy sections. PCA analysis highlights pronounced differences in amide groups of proteins, particularly alpha and beta structures, and in phospholipid moieties.

Conclusions

Infrared spectroscopy emerges as a powerful tool for probing molecular responses in squamous cell carcinoma. Providing unique molecular information, it aids in early diagnosis, real-time monitoring of treatment efficacy, and precise tumor margin assessment. Continued research and technological advancements could integrate this method into routine clinical practice, ultimately enhancing the management and outcomes for SCC patients.

Therapeutic peptides have emerged as a promising frontier in the development of anti-cancer agents, classified into three main groups: antimicrobial/pore-forming peptides, cell-permeable peptides, and tumor-targeting peptides. This classification, delineates the diverse cellular targets of these peptides, offering a comprehensive perspective on their potential applications in cancer treatment. Antimicrobial/pore-forming peptides (AMPs) represent a subset of these therapeutic peptides with natural occurrences across living organisms, integral to the innate immune defense mechanism. This study focuses on a bioassay-guided fractionation approach to purify a bioactive peptide (PAP) from the soft body tissue of marine gastropod T. radiatus, highlighting its multifaceted properties, utilizing sequential procedures such as ammonium sulfate precipitation, cation exchange chromatography, and gel filtration chromatography. The purified antibacterial peptide (PAP), exhibited exceptional efficacy against both Gram-positive and Gram-negative bacteria, particularly demonstrating sensitivity towards E. faecium, K. pneumoniae, and S. dysenteriae. Further characterization revealed PAP's stability across broad pH and temperature ranges, serum stability, and the ability to form membrane pores, as evidenced by SEM analysis. PAP displayed stability across diverse conditions and the ability to form membrane pores, suggesting a potent antimicrobial mechanism. Significantly, PAP demonstrated noteworthy anticancer activities by inhibiting proliferation in lung cancer cell lines (A549 and NCI-H460) in a concentration-dependent manner, while exhibiting non-cytotoxicity to normal cells. This selective anticancer effect was further evidenced by the promotion of angiogenesis in chick embryos. The amino acid sequence of PAP (MSMGSFGFALAVMVLAVLVASAAGAPNTNLVSSACNGNKIPSGNPFFNNLGALLVDLEK) and its three-helix structure with an extended loop were determined through MALDI-TOF-MS/MS analysis and in-silico modeling, respectively.
In conclusion, this research unveils the multifaceted nature of the bioactive peptide from T. radiatus, emphasizing its dual-action as a potent antimicrobial agent and a selective anticancer drug candidate. These findings underscore the potential therapeutic significance of marine peptides in addressing global health challenges, particularly in the context of antimicrobial resistance and cancer treatment.

[Background] Boron neutron capture therapy (BNCT) is a particle beam therapy that enables the precise targeting of tumors at the cellular level. Drawing on the success observed in nuclear reactors, BNCT holds promise as a therapeutic approach for addressing invasive brain tumors, such as malignant gliomas and high-grade meningiomas.

Chordomas are rare bone tumors characterized by locally invasive, frequent recurrence, and relative radioresistance. Recently, treatment modalities, including proton or carbon ions particle irradiation, have been developed; however, conclusive evidence supporting their efficacy is yet to be established. This experimental study aimed to evaluate the effectiveness of BNCT in the treatment of chordoma.

[Methods] The U-CH1 and JHC7 human chordoma cell lines were employed in this study. In the in vitro experiment, both cell lines were exposed to p-boronophenylalanine (BPA) at a concentration of 10 µg boron/ml for duration of 3, 6, and 24 hours. Subsequently, the measurement of cellular boron uptake was conducted using Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES). After 24 hours of exposure, the medium was replaced with a boron-free medium, and the subsequent investigation was focused on boron clearance. Neutron irradiation was then applied to these two cell lines, BNCT with BPA (10 µg Boron/ml for a 24-hour exposure before irradiation) (BNCT group), and neutron irradiation without BPA (hot control group), for 0 to 30 minutes. Assessment of the cell-killing effect was carried out using a colony forming assay. In the in vivo experiment, subcutaneous tumor-bearing mice were intravenously administered BPA (250mg/mouse body weight). After 1 hour, the mice were sacrificed, and the boron concentrations in both the tumor and each organ were measured using ICP-AES.

[Results] In the in vitro BPA exposure experiment, U-CH1 exhibited an increase in cellular boron uptake with prolonged BPA exposure time, whereas JHC7 demonstrated a consistent uptake unaffected by exposure time. Both cell lines showed a rapid decrease in cellular boron concentration after incubation with boron-free medium. Neutron irradiation revealed that the BNCT group demonstrated a more pronounced cell-killing effect than the hot control group in both cell lines. In the in vivo biodistribution of boron, the tumor accumulation was 5.7 µg B/g with a tumor-to-blood ratio (T/Bl) of 1.3 in U-CH1, while JHC7 showed a tumor accumulation of 9.3 µg B/g, with a T/Bl of 1.5.

[Conclusions] Despite the relatively low intracellular boron uptake compared to other malignant tumors, these findings suggest that BNCT may represent an effective approach in the management of chordoma. Future efforts will include in vivo neutron irradiation experiments to more fully assess the effects of BNCT on survival and neurological function.

Protein homeostasis or proteostasis is achieved through a dynamic balance between protein synthesis and degradation. The ubiquitin proteasome pathway is responsible for the breakdown of approximately 80% of intracellular proteins. The protein is firstly tagged by ubiquitin molecules, and then targeted for degradation by the proteasome. Abnormalities in protein synthesis, folding, transportation, degradation, chromosomal imbalance, oncogenic activation, and translation errors can lead to an imbalance in the protein homeostasis and result in a wide range of human illnesses and diseases, such as cancer, autoimmune diseases, and neurodegenerative disorders.

Proteasome inhibition has emerged as a powerful strategy for anti-cancer therapy. The constitutive proteasome, commonly referred to as the 26S proteasome, is a large, multicatalytic enzyme complex of approximately 2.5 MDa, consisting of a 20S catalytic core particle made up of seven α subunits (α 1-7) and seven β subunits (β 1-7), with catalytic protease activity residing in the β1, β2, and β5 subunits. The 20S core is associated with one or two regulatory particles, which could be 19S (PA700), which is ATP-dependent, as well as 11S (PA28, PA26, REG) or PA200 which are ATP-independent.

Proteasome inhibitors mediate their apoptotic effect in tumor cells via the inhibition of NFκB activity, inhibition of angiogenesis and DNA repair, altered degradation of cell-cycle-related proteins, altered pro-apoptotic and anti-apoptotic protein balance, and endoplasmic reticulum stress.

Ridaifen (RID) compounds are tamoxifen (TAM) analogues, with RID-F featuring two homopiperidine moieties on rings B and C. RID-F was the most effective in inhibiting all three proteasome functions, which are chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-peptidyl glutamyl peptide hydrolase (PGPH).

Besides the established role of proteasome inhibitor (PI) drugs in the treatment of hematological malignancies such as multiple myeloma and mantle cell lymphoma, PIs have emerged as promising drug candidates for other conditions, including neurodegenerative disorders, inflammation, immune diseases, ischemic stroke, and tuberculosis.

In light of this, we report the design and synthesis of novel ridaifen analogues that target the proteasome enzyme. The synthesized analogues maintained the triphenylethylene scaffold of ridaifen, while varying the substituents on rings A, B and C.

Purpose

To assess the effectiveness of avoidance structure (AS) techniques, alone and in combination with jaw-tracking (JT) techniques, in the treatment of sinonasal cancer, with the aim of minimizing radiation exposure to the lens.

Methods

Thirty patients were included in the study, and three sets of intensity-modulated radiation therapy (IMRT) plans were designed in an Eclipse treatment planning system: (1) original plans (O-Ps) with seven non-coplanar fields were optimized to meet clinical criteria; (2) duplicated O-Ps were re-optimized using the AS technique (AS-P), specifically for lens structures while keeping other optimization conditions consistent; and (3) utilizing both AS and JT techniques to generate a third set of plans (AS-JT-P). Dosimetric parameters, including dose to target volume and organs at risk (OARs), were evaluated. Additionally, the Lyman—Kutcher—Burman (LKB) model was utilized to predict the normal tissue complication probability (NTCP) of OARs. The data from three sets of treatment plans were collected and compared.

Results

Compared to O-P, the average reduction of D_2% for the lens in AS-JT-P was approximately 2-3 Gy, with a corresponding average NTCP reduction of 0.1-0.3%. The AS-P reduced the D_2% of the contralateral lens by approximately 1Gy. The differences mentioned above were statistically significant (P<0.05). Additionally, the AS technique resulted in a slight deterioration in dose uniformity and conformity for the target volume, with minimal impact on other OARs.

Conclusions

The combination of AS and JT techniques can effectively minimize the radiation exposure to the lenses, reducing the risk of radiation-induced cataract. The use of AS and JT techniques is recommended in clinical practice for the treatment of sinonasal cancer.

Targeting cancer stem cells (CSCs) in anticancer discovery is very difficult due to the resistance of CSCs to conventional drugs, their low proliferation rate, improved DNA damage repair, and the overexpression of anti-apoptotic proteins and multidrug resistance transporters. Different CSC targets, such as the ABC cassette, surface markers, signal cascade, and tumour microenvironment, are involved in the interruption of cell signaling pathways that are critical for the survival and functioning of the CSC population. The study aims to identify potential drug-like phytotoxic alkaloids with anticancer activity from the toxic plants-phytotoxins (TPPTs) database. A total of 1586 phytotoxins were filtered to obtain 653 alkaloids. Lipinski's properties and the TPSA of alkaloids were predicted for drug likeness and toxicity based on various organ endpoints. Compounds that obeyed Lipinski’s rule of five, with moderate or no toxicity and an LD₅₀ of >2000 mg/kg, were selected. The 12 drug-like phytotoxic alkaloids obtained from the filtering were docked on an isomerase-perdeuterated E65Q-TIM protein (ID: 7AZA; resolution = 1.10 Å) cocrystallized with phosphoglycolohydroxamate. The best binding poses were ranked using their binding energies (E) and inhibition constants (Ki). An evaluation of the protein—ligand's best conformational poses allowed us to identify three alkaloids (norcoclaurine, palustridiene, and apovincamine) with Ki < 1.00 µM and E < -9.00 kcal/mol. All the docked ligands could bind more efficiently to the isomerase-perdeuterated E65Q-TIM protein than the co-crystallized phosphoglycolohydroxamate. Significant protein—ligand binding interactions also occurred for (-)-eburnamonine (E = -8.03 kcal/mol; Ki = 1.30 µM) and retamine (E = -7.81 kcal/mol; Ki = 1.89 µM). The efficient inhibition of perdeuterated E65Q-TIM in CSCs usingphytotoxic alkaloids provided more insights into understanding the mechanisms of the anticancer activity of phytotoxic alkaloids.

Background: Proton-pump inhibitors (PPIs) have raised concerns regarding an increased risk of gastric cancer.

Aim: This study aims to evaluate the association between PPI use and the risk of gastric cancer.

Methods: A systematic search of Medline/PubMed, Embase, and Scopus databases was conducted to identify both randomized and non-randomized studies examining the link between PPIs and gastric cancer. Histamine-2 receptor antagonist (H2RA) users were chosen as controls to minimize confounding by indication and focus on patients requiring gastric acid suppression. Two authors independently extracted data and assessed bias risks. Maximally-adjusted relative risk (RR) estimates were extracted, and random- and fixed-effect models calculated summary estimates. Heterogeneity and small-study effects were examined, and GRADE was used to evaluate evidence certainty.

Results: Of 8375 records, 12 non-randomized studies (>6 million patients; 11,554 gastric cancers) and two randomized clinical trials (498 patients; 1 gastric cancer) met eligibility criteria. Randomized evidence provided very-low certainty evidence. Meta-analysis of six adequately adjusted non-randomized studies (2.5 million patients; 7372 gastric cancers) revealed no association between PPIs and gastric cancer (RR_random = 1.07, 0.97-1.19; RR_fixed = 1.05, 0.98-1.12), with low certainty of evidence. No convincing evidence of dose-response or increased risk with long-term use was found. Lack of or minimal adjustment for confounding was associated with larger effect sizes.

Conclusions: Non-randomized studies with adequate confounding control found no association between PPIs and gastric cancer. Previous published studies indicating an increased risk of gastric cancer associated with PPIs may suffer residual confounding.

Introduction

Neuroblastoma (NB) is a pediatric tumor composed of adrenergic (ADRN) and mesenchymal-like (MES) cells which derive from the dysregulation of normal cell differentiation imposed by NB Core Regulatory Circuitries (CRCs). We hypothesize that somatic single-nucleotide variants (SNVs) in active CRCs transcription factor binding sites (aTFBSs) may underlie such perturbation, promoting NB tumorigenesis. We aim to investigate such patterns of regulatory elements and identify putative driver SNVs, exploring their role in NB.

Methods

MES and ADRN aTFBSs were identified by integrating 42 ChIP-seq and 12 ATAC-seq experiments in 7 ADRN and 2 MES NB cell lines. Using the Fisher test, we tested these regions for an enrichment of somatic SNVs obtained from the WGS data of 397 NB patients. SNVs were selected based on their impact on CRC TF binding through the FABIAN-variant tool. Next, aTFBS target genes were identified by analyzing the promoter capture HiC (CHiC) in 2 ADRN and 2 MES NB cell lines and their expression values were correlated with clinical and survival data of a second cohort of 498 NBs.

Results

We found six aTFBS sets of significantly enriched TFs (FDR ≤ 0.1) in SNVs, i.e., 5 ADRN (GATA3, HAND2, ISL1, MYCN, and TBX2) and 1 MES (FOSL2), with 689 mutations impacting the binding of CRC TFs (Fabian ≠ 0). Mutated aTFBSs were found to interact with genes of neuronal differentiation pathways and proliferated MES cells , suggesting the potential impact of SNVs on NB cell identities. By focusing on genes of developmental and differentiation processes interacting with aTFBSs carrying SNVs with the highest (cut-off ≥ 0.1) or lowest (cut-off ≤ -0.1) Fabian score, we found targets (ROBO2, CACNB1, PIK3R1, MDGA1, HES6, LDLRAD4, DGUOK, IRX1, and SPOCK2) whose expression significantly correlated with worse NB outcomes (FDR ≤ 0.05).

Conclusions

These results demonstrated that somatic noncoding SNVs may act synergistically to affect NB CRCs and thus contribute to tumorigenesis.

Introduction

Knowing how to accumulate boron into the tumor cells is a crucial aspect of boron neutron capture therapy (BNCT), which can be targeted at the cellular level, and the development of novel boron agents other than BPA, which is used in clinical practice, is urgently needed. Our previous work demonstrated the efficacy of BNCT in malignant gliomas using PBC-IP, a pteroyl-closo-dodecaborate-conjugated 4-(p-iodophenyl) butyric acid with folate receptor targeting. Administered through convection-enhanced delivery (CED), PBC-IP resulted in long-term survival equivalent to cure, surpassing BPA outcomes. While the local administration method has been employed for the treatment of brain tumors using this drug, its applicability extends to cancers in other organs throughout the body through intravenous administration. Consequently, this report emphasizes the safety of BNCT treatment with this drug, examining both local dosing in the brain and intravenous administration in the experimental investigation. This study focuses on assessing PBC-IP's safety in CED procedures and implications for clinical application.

Methods

PBC-IP was administered intravenously or via CED to normal Fischer rats. At the predetermined time, each organ was collected and boron concentration was measured via Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES). The intravenous administration of PBC-IP aimed to evaluate toxicity in cases where the tip of the CED catheter was implanted in the normal brain or accidentally inserted into a blood vessel. Additionally, CED administration of PBC-IP to normal rats aimed to evaluate the extent of drug clearance from normal tissues. PBC-IP concentrations were set at a maximum of 5000 μg B/mL for intravenous administration and 1500 μg B/mL for CED.

Results

Upon PBC-IP administration intravenously, no indications of apparent toxicity were observed in post-administration assessments. Furthermore, the boron concentration in each organ was within acceptable limits. The maximum boron concentration was 10.3 ± 0.8 μg B/g in the liver at a dose of 200 μL of PBC-IP 5000 μg B/mL. The boron concentration in the brain on the same side as PBC-IP CED administration exhibited a gradual decrease, while boron concentrations in other organs were minimal (the boron concentrations in each organ were less than 1 μg B/g).

Conclusions

Safety assessments revealed no apparent toxicity with intravenous administration, and acceptable boron concentrations in organs. CED administration exhibited gradual brain boron reduction, minimizing concentrations in other organs. Furthermore, the potential of BNCT with intravenous administration of this drug for cancers in organs other than the brain has been explored, and the safety of the drug in such scenarios has been established. PBC-IP emerges as a non-toxic, swiftly cleared boron agent, offering promise for BNCT applications. Future clinical prospects are encouraging, positioning PBC-IP as a potential breakthrough in boron neutron capture therapy.

Background:

Galectins are immune system regulators, associated with disease progression in cancer. This research aims to investigate the correlation between mutated cancer-critical genes and galectin levels in breast cancer patients to determine whether galectins and genetic profiles can be used as biomarkers for disease and potential therapy targets.

Materials and Methodology:

Prisma Health Cancer Institute’s Biorepository provided sixty-five breast cancer patient samples, including all four stages as well as major molecular subtypes of breast cancer. Hotspot mutation statuses of cancer-critical genes were determined using multiplex PCR in tumor samples from the same patients.

The galectin levels of patients’ sera were analyzed using an enzyme-linked immunosorbent assay (ELISA) to measure the concentrations of galectins-1, -3, and -9. Two-sample t-tests (α=0.05) were performed using JMP software.

Results:

Our analysis indicates that KIT mutations correlate with elevated levels of galectin-1 and -9, while TP53 mutations correlate with elevated galectin-3 levels. In patients with the Luminal A subtype, FLT3 mutation is correlated with lower galectin-1 and -9 levels, TP53 mutations correlate to higher galectin-3 levels, and MET mutations correlate to higher galectin-9 levels. Patients with Invasive Ductal Carcinoma had significantly higher levels of galectin-3 than patients with Ductal Carcinoma in Situ.

Patients with both TP53 and KIT mutations exhibit elevated galectin-3 levels, while patients with one or neither mutation show no significant differences in galectin-3 levels. Similar trends were observed for patients with both TP53 and PIK3CA mutations compared to those with one or neither mutation.

In addition, metastatic breast cancer samples were more likely to have KIT or PIK3CA mutation compared to primary breast cancer samples.

Conclusion:

The relationship between genetic mutations and galectin levels will potentially identify appropriate candidates for combined therapy which targets genetic mutations and galectins, aiding the search for biomarkers used for breast cancer diagnosis, disease progression, and prognosis.