Prognostic gene biomarkers for c-Src inhibitor Si162 sensitivity in melanoma cells.

Background/aim: Early detection and treatment are crucial in combating malignant melanoma. Src is an important therapeutic target in melanoma due to its association with cancer progression. However, developing effective Src-targeting drugs remains challenging and personalized medicine relies on biomarkers and targeted therapies for precise and effective treatment. This study focuses on Si162, a newly synthesized c-Src inhibitor, to identify reliable biomarkers for predicting Si162 sensitivity and explore associated biological characteristics and pathways in melanoma cells. Materials and methods: Primary melanoma cells (M1, M21, M24, M84, M133, M307, and M2025) were obtained from patients diagnosed with melanoma. Si162 cytotoxicity tests were performed using luminescent adenosine triphosphate detection and the half-maximal inhibitory concentration (IC50) values were calculated. Gene expression profiles were analyzed using microarray-based gene expression data. Differentially expressed genes between the resistant and sensitive groups were identified using Pearson correlation analysis. Gene coexpression, interactions, and pathways were investigated through clustering, network, and pathway analyses. Biological functions were examined using the Database for Annotation, Visualization, and Integrated Discovery. Molecular pathways associated with different responses to Si162 were identified using gene set enrichment analysis. The gene expressions were validated using reverse transcription-quantitative polymerase chain reaction. Results: The cells revealed significant differences in response to Si162 based on the IC50 values (p < 0.05). A total of 36 differentially expressed genes associated with Si162 susceptibility were identified. Distinct expression patterns between the sensitive and resistant groups were observed in 9 genes (LRBA, MGMT, CAND1, ADD1, SETD2, CNTN6, FGF18, C18orf25, and RPL13). Coexpression among the differentially expressed genes was highlighted, and 9 genes associated with molecular pathways, including EMT, transforming growth factor-beta (TGF-ß) signaling, and ribosomal protein synthesis, between groups. Genes involved in dysregulated immune response were observed in the resistant group. The involvement of 5 genes (ADD1, CNTN6, FGF18, C18orf25, and RPL13) in Si162 resistance was confirmed through qRT-PCR validation. Conclusion: These findings contribute to our understanding of the underlying biological differences among melanoma cells and suggest potential biomarkers and pathways associated with Si162 response and resistance.

The probiotic-induced disregulation of immune-related genes in colon cells and relation with colorectal cancer.

Supplemental probiotics available without a doctor's prescription have become a booming global market in past few years. Medical research has shown that probiotics may benefit both healthy people and cancer patients by improving their immune systems and digestive health. Even though they seldom produce serious side effects, it's important to note that they are generally safe to use. But further investigation into the role of probiotics and gut microbes in the etiology of colorectal cancer is required. Here we used computational methods to identify the transcriptome alterations induced by probiotic treatment of colon cells. The impacts of genes with substantially altered expression were assessed in relation to the progression of colorectal cancer. Following probiotic treatment, substantial and high-level changes in the expression of genes were determined. BATF2, XCL2/XCL1, RCVRN and, FAM46B were up-regulated while IL13RA2, CEMIP, CUL9, Cand XCL6, PTCH2 were down-regulated in probiotic-treated colonic tissue and tumor samples. Also, immune-related pathways were determined that contribute to colorectal cancer formation and progression, as well as genes with opposing roles. This suggests that the length and dosage of probiotic use, in addition to the specific bacterial strain, maybe the most important determinants in the association between probiotics and colorectal cancer.

NK-cell dysfunction of acute myeloid leukemia in relation to the renin-angiotensin system and neurotransmitter genes.

Acute myeloid leukemia (AML) is the most heterogeneous hematological disorder and blast cells need to fight against immune system. Natural killer (NK) cells can elicit fast anti-tumor responses in response to surface receptors of tumor cells. NK-cell activity is often impaired in the disease, and there is a risk of insufficient tumor suppression and progression. The aim of this study is to assess the dysfunction of NK cells in AML patients via focusing on two important pathways. We obtained single-cell RNA-sequencing data from NK cells obtained from healthy donors and AML patients. The data were used to perform a wide variety of approaches, including DESeq2 (version 3.9), limma (version 3.26.8) power differential expression analyses, hierarchical clustering, gene set enrichment, and pathway analysis. ATP6AP2, LNPEP, PREP, IGF2R, CTSA, and THOP1 genes were found to be related to the renin-angiotensin system (RAS) family, while DPP3, GLRA3, CRCP, CHRNA5, CHRNE, and CHRNB1 genes were associated with the neurotransmitter pathways. The determined genes are expressed within different patterns in the AML and healthy groups. The relevant molecular pathways and clusters of genes were identified, as well. The cross-talks of NK-cell dysfunction in relation to the RAS and neurotransmitters seem to be important in the genesis of AML.

Ulipristal-temozolomide-hydroxyurea combination for glioblastoma: in-vitro studies.

BACKGROUND: Glioblastoma multiforme (GBM) is a brain malignancy with worst survival. Low dose progesterone stimulates GBM growth, while progesterone receptor (PR)-antagonist mifepristone was shown to reduce growth and to enhance temozolomide sensitivity in GBM cells. Mifepristone is not available in all countries due to ethical reasons and may cause adrenal insufficiency and pelvic infections. Ulipristal is also a PR-antagonist used in treatment of uterine leiomyomas with higher biosafety. Ulipristal is demonstrated to suppress growth of breast cancer, yet it is not tested as yet whether it can also block growth and sensitize to temozolomide in glioblastoma as it was previously shown with mifepristone. Our first aim was to detect whether ulipristal exerts antiproliferative and chemotherapy-sensitizing effects in glioblastoma. Hydroxyurea inhibits DNA replication via blocking ribonucleotide reductase (RR) and it was demonstrated to increase temozolomide antineoplasticity in GBM. Progesterone receptor-activation in the uterus enhances RR transcription. Hence, we have hypothesized that PR-inactivation with ulipristal would further enhance hydroxyurea antineoplasticity by shutting down DNA synthesis mechanisms through further suppression of RR. Lastly, there exists no study as yet whether ulipristal, hydroxyurea and temozolomide could exert ternary antineoplastic efficacy, which was our last aim to define. METHODS: To reveal interactions between ulipristal, hydroxyurea and temozolomide, we treated human U251 GBM cell line with these agents alone and in combination and measured cell proliferation, total antioxidant capacity (TAC) and total oxidant status (TOS) in conditioned medium and cellular cytokine gene expressions. RESULTS: All agents significantly reduced cell proliferation significantly, yet the most significant decrease of GBM cells occured with the triple drug combination at the 96th hour. All agents significantly decreased TAC and increased TOS in culture media, which was mostly relevant for the triple combination at the 96th hour. All these 3 agents tend to reduce the expression of immunosuppressive and/or GBM-growth stimulating cytokines TGFß, IL-10 and IL-17 while increasing the expression of GBM-growth suppressing cytokine IL-23. CONCLUSIONS: Repurposal of these agents in treatment of GBM would be a plausible approach if future studies prove their efficacy.

Neuroprotective effect of bromelain in 6-hydroxydopamine induced in vitro model of Parkinson's disease.

BACKGROUND: This study was designed to investigate the neuroprotective effects of bromelain, which is known to have anti-oxidant and anti-inflammatory properties, against the neurotoxicity (induced by 6-OHDA) in SH-SY5Y cells. METHODS AND RESULTS: To establish Parkinson's Disease (PD) model in cell culture conditions, SH-SY5Y cells were exposed to 200 µM 6-OHDA for 1 day. Prior to 6-OHDA treatment, SH-SY5Y cells had been pre-treated with bromelain (25 µg/mL, 50 µg/mL, 75 µg/mL and 100 µg/mL). After 1 day, cell viability was determined with the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assays. Oxidative stress was assessed with total antioxidant capacity (TAC), total oxidant status (TOS), glutathione reductase (GR) and malondialdehyde (MDA) analyses. The effect of the bromelain in SH-SY5Ycells was also examined by 4',6-diamidino-2-phenylindole (DAPI) staining. We found that 6-OHDA increased LDH leakage, and cellular apoptosis in SH-SY5Y cells. 6-OHDA aggravated oxidative stress by increasing TOS, MDA and GR and eventually promoted apoptosis in SH-SY5Y cells, while pretreatment with bromelain attenuated these toxic effects of 6-OHDA. CONCLUSIONS: These findings indicated that bromelain, with its neuroprotective features can be useful for neuroprotection in PD.

Effectiveness of Canakinumab Treatment in Colchicine Resistant Familial Mediterranean Fever Cases.

Anti-interleukin 1 agents are used successfully in colchicine-resistant or intolerant Familial Mediterranean Fever (FMF) patients. Sixty-five patients with FMF who received canakinumab treatment for at least 6 months due to colchicine resistance or intolerance between 2016 and 2020 in our department were retrospectively analyzed. Canakinumab treatment was given subcutaneously every 4 weeks. After completing monthly canakinumab therapy over 12 months, in patients with complete remission, the dosing interval was extended to every 1.5 months for 6 months, then every 2 months for 6 months, and finally every 3 months for a year. In patients without disease activation, canakinumab treatment was discontinued at the end of 3 years and followed up with colchicine treatment. Patients who had a flare switched to the previous dosing interval. In patients with renal amyloidosis, monthly canakinumab treatment was continued without extending the dose intervals. The mean duration of canakinumab use in our patients was 31.4 ± 10.57 months (6-52 months). The mean age at onset of symptoms was 4.65 ± 3.84 (range, 1-18) years, and the mean age at diagnosis was 5.59 ± 3.9 (range, 4-19) years. Complete remission was achieved in 57 (87.6%) and partial remission in seven (10.7%) patients. One patient was unresponsive to treatment. Canakinumab treatment was discontinued in three patients with complete remission and one patient with drug resistance. Erythrocyte sedimentation rate (ESR) (51.85 ± 15.7 vs. 27.80 ± 13.73 mm/h) and C-reactive protein (CRP) [26 (3-73) vs. 5 (1-48) mg/L] values were compared before and after canakinumab treatment in attack-free periods, a significant decrease was found after canakinumab treatment (p < 0.001, p < 0.001, respectively). Bodyweight Z-scores (respectively -0.80 ± 0.86 vs. -0.49 ± 0.92) were compared, similarly, a statistically significant increase after canakinumab treatment (p < 0.001), but no significant increase in height Z scores (-1.00 ± 0.88 vs. -0.96 ± 0.94) (p = 0.445) was detected. Four patients had FMF-related renal amyloidosis. The decrease in proteinuria with canakinumab treatment was not statistically significant (p = 0.068). Cervical lymphadenitis developed in one and local reactions in two patients. No severe adverse effects requiring discontinuation of canakinumab treatment were observed. Our study showed that canakinumab treatment was highly effective, well-tolerated in pediatric FMF patients, and controlled extension of the canakinumab dose interval was safe.

A Skeptical Approach to the Management of Persistent Oral Ulceration in a Child.

The diagnosis of oral lesions is sometimes difficult due to both the clinician's limited experience with the conditions that may cause the lesions and their similar appearances, especially in children. Correctly establishing a definitive diagnosis is of major importance to clinicians who manage patients with oral mucosal diseases. In patients with Fanconi anaemia (FA), oral ulcers occur frequently, which are quite variable, and may lead to a misdiagnosis or failure to diagnose. Here, we report the case of a 15-year-old boy who was examined for squamous cell cancer of the tongue and diagnosed as having FA without any haematological manifestations. While surgery could not be done, both radiotherapy and chemotherapy had to be decreased. He died of progressive disease 6 months after the diagnosis. Unexplained ulcers in a child with a duration longer than 2 weeks should be further evaluated, especially for FA, even without the presence of anaemia.

[A mourning case that referred with sexual identity disorder secondary to a general medical condition]. / Genel Tibbi Duruma Ikincil Cinsel Kimlik Bozuklugu Ile Basvuran Yas Olgusu.

D.G. was a 59-year-old male patient who was retired and married, and had 3 children. He reported no psychopathology prior to a myocardial infarction he had in 1996. Following bypass surgery he had erectile dysfunction. Subsequently, gynecomastia developed as a side effect of spironolactone and digoxin treatment. After a long period of depression he claimed was caused by non-adaptation to the changes in his body, he realized differences about himself; he began to feel like a woman. Upon referral to our clinic, he said that he had decided to continue his life as a woman and wished to get pink colored (as opposed to blue for male) identity card issued by the Turkish Government for female Turkish citizens. He reported that his wish was to learn how to become a woman. This is the first case in the medical literature defined as sexual identity disorder secondary to a general medical condition. The case is discussed in terms of pathological grief reaction.

[Levels of adenosine deaminase and dipeptidyl peptidase IV in patients with panic disorder]. / Panik bozuklugunda adenozin deaminaz ve dipeptidil peptidaz IV enzim düzeyleri.

OBJECTIVE: Adenosine deaminase and dipeptidyl peptidase IV are enzymes connected to T cells that play an important role in immune system functioning. In this study, in order to understand the immune processes in panic disorder, we determined the serum levels of adenosine deaminase and dipeptidyl peptidase IV in medication-free panic disorder patients and compared them to those of healthy controls. METHOD: Enzymes levels were determined in blood samples of 24 healthy controls and 33 panic disorder patients diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV that were medication free during the previous month and medically healthy. RESULTS: Levels of both enzymes were significantly higher in panic disorder patients than in the controls (P<0.001 for adenosine deaminase and P<0.05 for dipeptidyl peptidase IV). The levels of the enzymes did not correlate with sociodemographic variables, duration of the disorder, presence of agoraphobia, presence of stressors, number of panic attack symptoms, and Hamilton depression and anxiety rating scale scores. In addition, the 2 enzymes? levels did not correlate with each other. There was a correlation between Hamilton anxiety rating scale score and the number of panic attack symptoms (P<0.001); however, Hamilton anxiety rating scale scores were not correlated with the other variables. CONCLUSION: Our results suggest that there may be a primary or secondary impaired immune state in the course of panic disorder, as there is in many other psychiatric disorders, such as major depression. Future studies with larger samples are needed to clarify the relationship between the immune system and panic disorder.