Amino Acid Bitterness: Characterization and Suppression.

Amino acids are necessary for life, and many must be consumed because they cannot be endogenously synthesized. Typically, we eat them as proteins and peptides, which have little taste. However, we also directly ingest free amino acids, several of which are aversive because they elicit bitterness. This bitterness often prevents many patient populations from taking formulas and supplements containing free amino acids. Here, we characterize which amino acids are the most bitter, their concentration-intensity functions, and individual differences in bitterness perception, and we explore how sodium salts suppress the bitterness of amino acids. We found that the essential amino acids comprise the most bitter stimuli, with six of them conveying the most bitterness. Clustering and correlating amino acids by individual differences in bitterness perception show that there are approximately four groupings of amino acids and suggest that within these clusters, amino acids may be activating the same or overlapping TAS2Rs. We also show that bitterness can be largely suppressed by sodium salts for 5 of the 6 most bitter amino acids. These results hold promise for managing the bitter taste of nutritional supplements that contain amino acids and improving compliance.

Association between sidedness and survival among chemotherapy refractory metastatic colorectal cancer patients treated with trifluridine/tipiracil or regorafenib.

BACKGROUND: The impact of sidedness on survival of later-line treatment in patients with metastatic colorectal cancer (mCRC) is undetermined. This study aimed to investigate the association between sidedness and survival among chemotherapy refractory patients with mCRC treated with trifluridine/tipiracil (TAS-102) or regorafenib or both. PATIENTS AND METHODS: Patients with mCRC treated with TAS-102 or regorafenib between 2015 and 2020 was retrospectively collected. Patients were stratified into TAS-102 first and regorafenib first, then subdivided into TAS-102 followed by regorafenib (T-R) and regorafenib followed by TAS-102 (R-T) groups. The oncologic outcomes were presented with time-to-treatment failure (TTF) and overall survival (OS). RESULTS: After matching, 376 TAS-102 patients and 376 regorafenib patients were included for outcomes comparison. TTF had insignificant differences while OS was significantly different between TAS-102 and regorafenib groups. Median TTF and OS were 1.9 months versus 2.0 months (P = .701) and 9.1 months versus 7.0 months (P = .008) in TAS-102 and regorafenib, respectively. The OS benefits were consistent regardless primary tumor location. Subgroup analysis with 174 T-R patients and 174 R-T patients was investigated for treatment sequences. TTF and OS had significant differences in both groups. Median TTF and OS were 8.5 months versus 6.3 months (P = .001) and 14.4 months versus 12.6 months (P = .035) in T-R and R-T groups, respectively. The TTF and OS benefits were persisted regardless primary tumor location. CONCLUSION: TAS-102 first provided a better survival benefit in chemotherapy refractory patients with mCRC across all sidedness. Further prospective studies are warranted to validate our conclusions.

Investigating the relationship between lymphocyte cells apoptosis and DNA damage and oxidative stress and therapeutic and clinical outcomes of COVID-19 elderly patients.

BACKGROUND: While COVID-19 has been controlled and deaths have decreased, the long-term consequences of COVID-19 remain a challenge we face today. This study was conducted to determine the relationship between the apoptosis of lymphocyte cells with DNA damage and oxidative stress and the therapeutic and clinical outcomes of elderly patients with COVID-19. METHODS: This study was conducted from April 2020 to May 2021 (the period of severe attacks of the epidemic peak of COVID-19) and September 2022 (the post-COVID-19 period). The study groups included elderly patients with COVID-19 hospitalized in the ICU and normal wards of the hospital as well as elderly patients with influenza. A polymerase chain reaction was used to check the validity of the studied diseases. The Annexin V/Propidium Iodide method was used to evaluate the level of apoptosis. Genotoxic effects and DNA damage were assessed by the comet assay method. Total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase activity (MPO) were measured by photometric methods. RESULTS: The highest level of apoptosis in peripheral blood lymphocytes and the highest level of DNA damage were observed at both times in the intubated-ICU and non-intubated-ICU groups. In all groups, there was a significant increase in peripheral blood lymphocyte apoptosis levels and DNA damage levels compared to the healthy control group (p < 0.01). The level of apoptosis and DNA damage decreased significantly in the post-COVID-19 period (p < 0.01). In the investigation of oxidative stress biomarkers, the oxidative stress index, including TOS and MPO levels, increased in patients (p < 0.01), and the TAS level decreased (p < 0.01). CONCLUSION: It shows that the apoptosis of lymphocyte cells, DNA damage, and oxidative stress can be effective in prognostic decisions and is a suitable predictor for diagnosing the condition of patients with viral infections such as COVID-19 and influenza.

Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors.

Introduction: Protocadherin 9 (PCDH9), a member of the cadherin superfamily of transmembrane proteins, plays a role in cell adhesion and neural development. Recent studies suggest that PCDH9 may function as a tumor suppressor in certain cancers, though its specific role in breast cancer remains unclear. Methods: UALCAN database to retrieve information on PCDH9 expression in breast cancer tissues compared with that in normal tissues. The biological effects of PCDH9 in breast cancer cells were analyzed using the DepMap database. Stable knockdown or overexpression of PCDH9 in breast cancer cell lines and subsequently assessed tumor cell proliferation and migration. Synthetic lethal screening was conducted for breast cancer cells with low PCDH9 expression or deficiency. Results: In this study, we observed significant downregulation of PCDH9 in breast cancer tissues, with its expression negatively correlated with progression-free survival. Further investigations revealed that decreased PCDH9 expression promotes breast cancer cell proliferation and migration, while overexpression of PCDH9 has the opposite effect. Subsequently, we identified the TAS-102, an approved drug for metastatic colorectal cancer, exhibited selective cytotoxicity against breast cancer cells with low PCDH9 expression. Conclusion and discussion: In summary, our study identified PCDH9 as a tumor suppressor in breast cancer and highlighted TAS-102 as a potential therapeutic option for tumors with low PCDH9 expression or deficiency. The specific interaction between TAS-102 and PCDH9 warrants further exploration, providing deeper insights into its mode of action in treating PCDH9-deficient breast cancer.

Drought response of tuber genes in processing potatoes (Solanum tuberosum L.) in Japan.

BACKGROUND: Limited crop production due to lower rainfall has a major impact on the supply and demand of food for the human population. In potato (Solanum tuberosum L.), one of the major crops, there is also concern about a lack of production due to drought stress. Especially the cultivar "Toyoshiro" suitable for processing, has significant reduction in drought yield. Therefore, it is necessary to understand the mechanism of gene expression changes that occur in potato "Toyoshiro" plants and tubers during drought. METHODS AND RESULTS: Seed potatoes were split in half and one was used as a control plant (CT), and the other was used as a drought-stressed plant (DS). CT was watered daily, and DS watered off to mimic the weather conditions of the Tokachi-Obihiro region in 2021. These tubers were harvested at week 14 and the transcriptome was analyzed. DS plants showed 423 downregulated genes and 197 upregulated genes compared to CT. Factors related to cell wall modification, heat stress response, and phytosterol metabolism were detected among the genes whose expression changed. Moreover, the expression of "Abscisic acid and environmental stress-inducible protein TAS14 like (TAS14)," a molecule reported to be upregulated under drought stress, was also upregulated, and was upregulated expression in all strains that reproduced drought. The localization of this molecule in the nucleus and plasma membrane was confirmed in a mCherry-tagged TAS14 mutant line. CONCLUSIONS: Our findings contribute to understanding the survival strategy system of Japanese processing potatoes in response to drought stress.

Exploring the Role of the TAS2R16 Protein and Its Single Nucleotide Variants in Pituitary Adenoma Development.

BACKGROUND: Pituitary adenoma (PA) is a common benign tumor that develops in the pituitary gland, causing hormonal imbalances and potential health issues. The TAS2R16 gene codes for a taste receptor and is involved in bitter taste perception, but there is currently no known direct link between this gene and pituitary adenoma. METHODS: This study included 221 healthy controls and 131 patients with pituitary adenoma (PA) from the Lithuanian population. DNA was isolated from peripheral venous blood using the salt precipitation method. Genotyping was performed via RT-PCR. Statistical analysis was conducted with IBM SPSS Statistics 29.0 software, incorporating the Bonferroni correction for multiple comparisons. RESULTS: This study found that the TAS2R16 rs978739 C allele is less common in the non-invasive PA group compared to the control group (p = 0.045). The TAS2R16 rs860170 CT genotype reduces the likelihood of developing non-invasive PA by 1.9-fold under the codominant (p = 0.024) and overdominant (p = 0.030) models. The odds of developing non-invasive PA are reduced by 2-fold under the dominant (p = 0.021) model for TAS2R16 rs860170 CT + CC genotypes and by 2-fold under the additive (p = 0.018) model for each TAS2R16 rs860170 C allele. The PA group had higher serum levels of TAS2R16 than the control group (p < 0.001). The present study found that patients with the TAS2R16 rs978739 TT or CT genotype had higher serum TAS2R16 levels and protein concentrations than healthy individuals (p = 0.025 and p = 0.019, respectively), and those with the AA or AG genotype of TAS2R16 rs1357949 had higher protein concentrations (p = 0.005 and p = 0.007, respectively). CONCLUSIONS: The TAS2R16 rs978739 C allele was less common in the non-invasive PA group compared to the control group, while the TAS2R16 rs860170 CT genotype was linked to a reduced likelihood of developing non-invasive PA. Additionally, the PA group showed higher serum levels of TAS2R16, and increased serum protein concentrations were observed in PA patients with specific TAS2R16 variants.

Enhancing Airway Management: A Comparative Study of Macintosh and TAS Scope in Difficult Intubations.

Background: Intubation is essential in anesthesia for patient safety, requiring accurate techniques for difficult airways. Achieving first-attempt success is crucial. This study evaluates traditional laryngoscopes, such as the Macintosh, versus advanced tools like the TAS Scope. Material and Methods: This observational study, conducted from April to August 2023 at Saveetha Medical College and Hospital, involved 60 patients aged 18-65. The two groups of Macintosh laryngoscope and TAS Scope 30 each are based on airway difficulty predictors and patient characteristics. Results: The TAS Scope group had a higher first-attempt success rate and easier intubation experiences according to Likert scale ratings. Conclusion: The study underscores the benefits of using advanced devices like the TAS Scope for difficult airway management, showing higher success rates and ease of use. These findings support the adoption of new technologies to enhance patient safety and intubation effectiveness.

The Role of Mannitol and Vitamin D in Ovarian Ischemia/Reperfusion Injury in Rats with Acute Abdominal.

This study was designed to investigate the effects of vitamin D and mannitol in an experimental rat ovarian torsion model. Thirty-two female Wistar albino rats were randomly classified as group 1: (sham), group 2: (detorsion), group 3: (detorsion + mannitol), group 4: (detorsion + vitamin D) and group 5: (detorsion + mannitol + vitamin D) (for each group n = 8). All groups were subjected to bilateral adnexal torsion for 2 h except for group 1. Bilateral adnexal detorsion was performed in all groups except for group 1. Groups 3 and 5 intraperitoneally received the injection of mannitol at a dose of 0.3 mg/kg 30 min before detorsion. Also, the group's 4 and 5 orally received vitamin D in a dose of 500 IU/kg/day for two weeks before torsion. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and proliferating cell nuclear antigen (PCNA) levels were analyzed. According to the histopathological analyses, ovarian tissue damage and follicle counting were evaluated. TOS, OSI and histopathologic score values of ovarian tissue were significantly lower in group 5 than groups 2, 3 and 4 (p < 0.05). The PCNA level was significantly higher in group 5 than in groups 2, 3 and 4 (p < 0.05). A strong negative correlation was found between OSI and PCNA in groups 2, 3, 4 and 5 (r = -0.92, p = 0.01; r = -0.98, p < 0.0001; r = -0.98, p < 0.0001 and r = -0.96, p = 0.0002, respectively). The numbers of primordial follicles in group 5 (p < 0.001) and primary follicles in group 4 (p < 0.001) were significantly higher when compared to group 2. Based on the results of this study, it could be suggested that combination treatment of mannitol with vitamin D is more effective in reversing tissue damage induced by ischemia-reperfusion (I/R) injury in the ovarian torsion model than administration of only an agent.

"Our similarities are different" The relationship between alexithymia and depression.

Alexithymia is a multi-faceted personality trait, which is the inability to recognize and describe emotions. It is associated with a multitude of mental health problems, and its implication for the diagnosis and treatment of depression remains unclear. The current study explored the nuances of the relationship between alexithymia and depression in a sample of 210 patients with depression. We assessed alexithymia with the 20-Item Toronto Alexithymia Scale (TAS-20) and depression with the Beck Depression Inventory (BDI-I). The mean TAS-20 score was 57.47 ± 10.63, and the mean BDI-I score was 49.33±9.24. We explored the network structure of alexithymia and depression. Items related to difficulties in identifying, describing, and expressing feelings were prominent in the alexithymia network. Joy, guilt, and self-dislike stand out in the depression network. In our analysis, we were able to show the crescent relationship between depression and alexithymia, with an inflection point at a TAS-20 score of 53. Although the correlation-concordance index was moderate (0.41; 95 %CI: 0.29-0.51), both scales greatly overlap. In the joint network of alexithymia and depression, we could identify bridge (i.e., connecting) items between alexithymia and depression. These were difficulties understanding and relating feelings to physical and body sensations on the alexithymia side, and self-dislike, crying, and somatic concern on the depression side. Taken together, they point to the pivotal role of alexithymia in the somatization/embodiment of emotions and feelings in depression.

Modulating the HSP90 control over NFκB/NLRP3/Caspase-1 axis is a new therapeutic target in the management of liver fibrosis: Insights into the role of TAS-116 (Pimitespib).

Aberrant activation of the NLRP3 inflammasome is recognized to induce a chronic inflammatory response in the liver, ultimately leading to hepatic fibrosis. HSP90 is suggested to regulate NLRP3 activation and its downstream signaling. This study is the first to explore the potential therapeutic role of pimitespib in mitigating liver fibrosis in rats. The results of the study revealed that pimitespib effectively suppressed hepatic inflammation and fibrogenesis by modulating HSP90's control over the NFκB/NLRP3/caspase-1 axis. In vitro experiments demonstrated that pimitespib reduced LDH levels and increased hepatocyte survival, whereas in vivo, it prolonged the survival of rats with hepatic fibrosis. Additionally, pimitespib exhibited improvements in the function and microscopic characteristics of rat livers. Pimitespib effectively inhibited NFκB, which serves as the priming signal for NLRP3 activation. Pimitespib's inhibitory effect on NLRP3, identified as an HSP90 client protein, plays a central role in the observed anti-fibrotic effect. The simultaneous inhibition of both priming and activation signals of NLRP3 by pimitespib led to a reduction in caspase-1 activity and subsequent suppression of the N-terminal fragment of gasdermin D, ultimately constraining hepatocyte pyroptotic cell death. These diverse effects were associated with a decrease in the transcription of inflammatory mediators IL-1ß, IL-18, and TNF-α, as well as the fibrogenic mediators TGF-ß, TIMP-1, PDGF-BB, and Col1a1. Moreover, pimitespib induced the expression of HSP70, which could further contribute to the repression of fibrosis development. In summary, our findings provide an evolutionary perspective on managing liver fibrosis, positioning pimitespib as a promising candidate for anti-inflammatory and antifibrotic therapy.

TAS2R38 Genotype Does Not Affect SARS-CoV-2 Infection in Primary Ciliary Dyskinesia.

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference (p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m2). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection.

Bitter-tasting drugs tune GDF15 and GLP-1 expression via bitter taste or motilin receptors in the intestine of patients with obesity.

OBJECTIVE: Growth differentiation factor 15 (GDF15), a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the hindbrain. Bitter compounds are known to induce satiety via the release of glucagon-like peptide 1 (GLP-1) through activation of bitter taste receptors (TAS2Rs, 25 subtypes) on enteroendocrine cells in the gut. This study aimed to investigate whether and how bitter compounds induce a stress response in intestinal epithelial cells to affect GDF15 expression in patients with obesity, thereby facilitating satiety signaling from the gut. METHODS: The acute effect of oral intake of the bitter-containing medication Plaquenil (hydroxychloroquine sulfate) on plasma GDF15 levels was evaluated in a placebo-controlled, double-blind, randomized, two-visit crossover study in healthy volunteers. Primary crypts isolated from the jejunal mucosa from patients with obesity were stimulated with vehicle or bitter compounds, and the effect on GDF15 expression was evaluated using RT-qPCR or ELISA. Immunofluorescence colocalization studies were performed between GDF15, epithelial cell type markers and TAS2Rs. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV3727; 2) determining TAS2R4/43 polymorphisms that affect taste sensitivity to TAS2R4/43 agonists. RESULTS: Acute intake of hydroxychloroquine sulfate increased GDF15 plasma levels, which correlated with reduced hunger scores and plasma ghrelin levels in healthy volunteers. This effect was mimicked in primary jejunal cultures from patients with obesity. GDF15 was expressed in enteroendocrine and goblet cells with higher expression levels in patients with obesity. Various bitter-tasting compounds (medicinal, plant extracts, bacterial) either increased or decreased GDF15 expression, with some also affecting GLP-1. The effect was mediated by specific intestinal TAS2R subtypes and the unfolded protein response pathway. The bitter-induced effect on GDF15/GLP-1 expression was influenced by the existence of TAS2R4 amino acid polymorphisms and TAS2R43 deletion polymorphisms that may predict patient's therapeutic responsiveness. However, the effect of the bitter-tasting antibiotic azithromycin on GDF15 release was mediated via the motilin receptor, possibly explaining some of its aversive side effects. CONCLUSIONS: Bitter chemosensory and pharmacological receptors regulate the release of GDF15 from human gut epithelial cells and represent potential targets for modulating metabolic disorders or cachexia.

Development of a structured interview for the modified version of the Beth Israel Hospital psychosomatic questionnaire for alexithymia.

Background: An observer-rated questionnaire for alexithymia based on the original 17-item Beth Israel Hospital Psychosomatic Questionnaire for Alexithymia (BIQ) was developed by Sifneos in 1973 and modified into a 12-item version of BIQ by Taylor et al. in 1997. However, it has rarely been used in a clinical or research context and studies have not given satisfactory inter-rater reliability for the 12-item version. Objective: To develop a structured interview in Japanese for the12-item modified version of BIQ (m-SIBIQ) to determine the reliability and validity of the m- scores and its factor structure model. Methods: Ninety-two Japanese young adults were interviewed. The inter-rater reliability of the m-SIBIQ was assessed by exploratory factor analysis. For the concurrent and convergent validities, correlation analysis was done between the scores of m-SIBIQ and the self-reported questionnaires: 20-Item Toronto Alexithymia Scale (TAS-20), NEO Five-Factor Inventory (NEO-FFI), Emotional Empathy Scale (EES), Interpersonal Reactivity Index (IRI), Beck Depression Inventory-II (BDI-II), and State-Trait Anxiety Inventory (STAI). Goodness of fit of the structure model of the m-SIBIQ was evaluated using confirmatory factor analysis, and the results were examined through stepwise multiple regression analysis. Results: Good reliability was obtained for the total score of m-SIBIQ: Cronbach's α.950 (p<.001) and ICC.75(p<.05). The validity of the factor structure was obtained by confirmatory factor analysis using covariance. The model of the alexithymia constructs was configured by the operative thinking (la pensée opératoire) and affect awareness components. The stepwise multiple regression analysis extracted the total score of m-SIBIQ as significantly, negatively correlated with the Openness to experience score of NEO-FFI and significantly, positively correlated with the emotionally chilly score of EES and the score of difficulty describing feelings (DDF) of TAS-20. There were no correlations between the m-SIBIQ and BDI-II scores. Conclusion: For Japanese young adults, the m-SIBIQ is a reliable and valid instrument for overcoming weaknesses of the self-reported procedures by bringing to light the alexithymia construct and principal dimensions.

Alexithymia as a mediator between adverse childhood events and the development of psychopathology: a meta-analysis.

Introduction: Victims of child abuse have an elevated risk of developing mental health issues later in life. Several variables have been suggested as mediators of this correlation, but little is known about the possible influence of alexithymia. Alexithymia is a sub-clinical personality trait that manifests as difficulties recognizing and verbalizing emotions. Methods: In this study, two separate meta-analyses were conducted using questionnaire data, and Pearson correlations for overall effects were estimated. Results: The correlation between child abuse and alexithymia showed to be significant (r = .26), as did the correlation between alexithymia and general psychopathology (r = .44). Further analyses revealed no indication for possible publication bias. When investigating differences between various subtypes of child maltreatment, each subtype significantly correlated with alexithymia. Emotional abuse, emotional neglect, and physical neglect had stronger correlations than physical and sexual abuse. Discussion: These results suggest that alexithymia plays a mediating role, at least in part, in the relationship between experiences of child abuse and general psychopathology in adulthood. Therefore, alexithymia may be relevant to further research and deserves attention in the prevention of and therapy for mental health issues in victims of child abuse.

"Lasagna"-Structured SnS-TaS2 Misfit Layered Sulfide for Capacitive and Robust Sodium-Ion Storage.

Stannous sulfide (SnS), a conversion-alloying type anode for sodium-ion batteries, is strong Na+ storage activity, a low voltage platform, and high theoretical capacity. However, grain pulverization induced by intolerable volume change and phase aggregation causes quick capacity degradation and unsatisfactory rate capability. Herein, a novel "lasagna" strategy is developed by embedding a SnS layer into the interlayer of an electrochemically robust and electron-active TaS2 to form a misfit layered (SnS)1.15TaS2 superlattice. For Na+ storage, the rationally designed (SnS)1.15TaS2 anode exhibits high specific capacity, excellent rate capability, and robust cycling stability (729 mAh cm-3 at 15 C after 2000 cycles). Moreover, the as-assembled (SnS)1.15TaS2 || Na3V2(PO4)3 full cells achieve robust and fast Na+ storage performance with ≈100% capacity retention after 650 cycles at 15 C, which also demonstrates good low-temperature performance at -20 °C with a capacity retention of 75% and 2 C high-rate charge/discharge ability.

Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.

Synthesis of new phenothiazine derivatives: Molecular docking, assessment of cytotoxic activity and oxidant-antioxidant properties on PCS-201-012, HT-29, and SH-SY5Y cell lines.

Phenothiazine (PTZ) derivatives have been acknowledged as versatile compounds with significant implications across various areas of medicine, particularly, in cancer research. The cytotoxic effects of synthesized compounds on both normal and cancerous cells, along with their oxidant-antioxidant properties, are pivotal factors in cancer treatment strategies. In the current study, eight new PTZ derivatives were synthesized and the compounds' cytotoxic activities were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay while the oxidant-antioxidant properties were evaluated by oxidative stress index (OSI) calculation in SH-SY5Y (a human neuroblastoma cell line), HT-29 (a human colorectal adenocarcinoma cell line), and PCS-201-012 (a human primary dermal fibroblast cell line) cells. Consequently, the half-maximal inhibitory concentration (IC50) values of compound 3a were determined to be 218.72, 202.85, and 227.86 µM while the IC50 values of compound 3b were defined to be 227.42, 199.27, and 250.11 µM in PCS-201-012, HT-29, and SH-SY5Y cells, respectively. Additionally, it was determined that the synthesized compounds demonstrated the lowest OSI in PCS-201-012 cells as compared to the other cell lines.

Third-line treatment and beyond in metastatic colorectal cancer: What do we have and what can we expect?

Colorectal cancer remains the third most common cancer worldwide and the second cause of cancer-related death. Treatment advances and precision oncological medicine for these tumours have been stalled in comparison to those for other common tumours such as lung and breast cancer. However, the recent publication of the SUNLIGHT trial results with the trifluridine/tipiracil (TAS-102)-bevacizumab combination and the irruption of new molecular targets with guided treatments have opened new possibilities in third-line metastatic colorectal cancer management. Anti-EGFR rechallenge, anti-HER2 targeted therapies or the promising results of Pressurised Intraperitoneal Aerosol Chemotherapy (PIPAC), are some of the available options that may modify what is presumably third-line colorectal treatment. Hereby, we present the evidence of the different treatment options in third-line colorectal cancer and beyond, as well as the possibilities of sequencing them.

Enhanced Superconductivity in 2H-TaS2 Devices through in Situ Molecular Intercalation.

The intercalation of guest species into the gap of van der Waals materials often leads to the emergence of intriguing phenomena such as superconductivity. While intercalation-induced superconductivity has been reported in several bulk crystals, reaching a zero-resistance state in flakes remains challenging. Here, we show a simple method for enhancing the superconducting transition in tens-of-nanometers thick 2H-TaS2 crystals contacted by gold electrodes through in situ intercalation. Our approach enables measuring the electrical characteristics of the same flake before and after intercalation, permitting us to precisely identify the effect of the guest species on the TaS2 transport properties. We find that the intercalation of amylamine molecules into TaS2 flakes causes a suppression of the charge density wave and an increase in the superconducting transition with an onset temperature above 3 K. Additionally, we show that a fully developed zero-resistance state can be achieved in flakes by engineering the conditions of the chemical intercalation. Our findings pave the way for the integration of chemically tailored intercalation compounds in scalable quantum technologies.

Influence of humic acid on the p-tert-Butylphenol removal efficiency by Spirodela polyrhiza-Tas13 association.

Plant-microbe remediation technique is considered as a promising technology in removal of organic pollutants and its remediation efficiency is largely affected by a variety of surrounding environmental factors. Humic acid (HA) is the complex organic substance ubiquitous in environment, which characterized by its surfactant-like micelle microstructure and various reaction activity. In our study, a plant-microbe association with high p-tert-Butylphenol (PTBP) degradation potential constructed by Spirodela polyrhiza and Sphingobium phenoxybenzoativorans Tas13 has been used, and the influence of HA on the PTBP degradation efficiency of S. polyrhiza-Tas13 association was investigated. The result showed that the presence of HA greatly improved PTBP removal efficiency of S. polyrhiza-Tas13. The reason accounted for this may be due to the presence of HA promoted bacterial cell propagation, altered bacterial cell wall permeability, increased catechol 2,3-dioxygenase (C23O) enzyme activity of strain Tas13, rather than increasing the colonization ability of strain Tas13 on to the root surface. This study will greatly facilitate the application of aquatic plant-microbe association in environmental remediation.