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Solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and nanoemulsion (NE) of lornoxicam (LRX) were prepared for the treatment of painful and inflammatory conditions of the skin. Compritol® 888 ATO, Lanette® O and oleic acid were used as solid and liquid lipids. SLN, NLC and NE were found physically stable at various temperatures for 6 months. Case I diffusional drug release was detected as the dominant mechanism indicating Fickian drug diffusion from nanoparticles and nanoemulsion. The highest rate of drug penetration through rat skin was obtained with NE followed by NLC, SLN and a gel formulation. Nanoformulations significantly increased drug penetration through rat skin compared to the gel (p < 0.05). Thus, SLN, NLC and NE of LRX can be suggested for relieving painful and inflammatory conditions of the skin

Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca 2+ channel. This causes cytosolic Ca 2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe 2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca 2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca 2+ /ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca 2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer., (© 2024. The Author(s).)

Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance., Significance: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1., (©2024 The Authors; Published by the American Association for Cancer Research.)

Resistance to endocrine therapy and CDK4/6 inhibitors, the standard of care (SOC) in estrogen receptor-positive (ER+) breast cancer, greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status, providing actionable targets for restoring SOC efficacy., (© 2023. The Author(s).)

Background: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors., Methods: Microarray, RNA sequencing, and single-cell RNA sequencing-based gene expression data from gastric tumors were obtained from public databases. Freshly frozen gastric tumors (n = 42) and matched FFPE (formalin-fixed, paraffin-embedded) (n = 40) tissues from a Turkish gastric cancer cohort were used for quantitative real-time PCR and immunohistochemistry-based assessments of gene expression, respectively., Results: A novel list of 20 prognostic genes was identified and used for the classification of gastric tumors into two major tumor subgroups with differential stromal gene expression ("Stromal-UP" (SU) and "Stromal-DOWN" (SD)). The SU group had a more mesenchymal profile with an enrichment of extracellular matrix-related gene sets and a poor prognosis compared to the SD group. Expression of the genes within the signature correlated with the expression of mesenchymal markers ex vivo. A higher stromal content in FFPE tissues was associated with shorter overall survival., Conclusions: A stroma-rich, mesenchymal subgroup among gastric tumors identifies an unfavorable clinical outcome in all cohorts tested.

Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease., (© 2023. The Author(s).)

Hepatocellular cancer (HCC) is a leading cause of cancer-related mortality worldwide, and chronic hepatitis B virus infection (CHB) has been a major risk factor for HCC development. The pathogenesis of HBV-related HCC has been a major focus revealing the interplay of a multitude of intracellular signaling pathways, yet the precise mechanisms and their implementations to clinical practice remain to be elucidated. This study utilizes publicly available transcriptomic data from the livers of CHB patients in order to identify a population with a higher risk of malignant transformation. We report the identification of a novel list of genes (PCM1) which can generate clear transcriptomic sub-groups among HBV-infected livers. PCM1 includes genes related to cell cycle activity and liver cancer development. In addition, markers of inflammation, M1 macrophages and gamma delta T cell infiltration are present within the signature. Genes within PCM1 are also able to differentiate HCC from normal liver, and some genes within the signature are associated with poor prognosis of HCC at the mRNA level. The analysis of the immunohistochemical stainings validated that proteins coded by a group of PCM1 genes were overexpressed in liver cancer, while minimal or no expression was detected in normal liver. Altogether, our findings suggest that PCM1 can be developed into a clinically applicable method to identify CHB patients with a higher risk of HCC development.

Objective: High-grade serous ovarian carcinoma (HGSC) is one of the major tumors of the gynecological system with a poor survival rate and variable microscopic appearance. It was suggested that SET (solid, pseudo-endometrioid and transitional-like) morphology in ovarian HGSC is predictably associated with BRCA deficiencies. In this study, we investigated the microscopic patterns and some immunohistochemical markers predicting the prognosis of serous carcinoma., Material and Method: We re-evaluated 305 HGSC ovarian resections morphologically and calculated the SET morphology percentages for each case. Morphological and immunohistochemical data correlated with the survival and post-treatment disease progression data., Results: The median age at diagnosis was 57 years and the median follow-up period was 3.1 years. The median overall survival (OS) of ovarian carcinoma in SET-predominant tumors (n=60) was 81 months, while for tumors with SET non-dominant morphology (n=63) and non-SET morphology (n=182) it was 59.7 and 44.7 months, respectively., Conclusion: Predominant (more than 50%) SET morphology was significantly associated with increased survival rates of HGSC. Immunohistochemically, p53, ERCC1, ER, and PR antibodies were applied and only PR antibody positivity was found to be associated with borderline statistical significance for increased survival rates. Our results suggest that SET morphology may be a potential predictive and prognostic marker in managing the treatment strategies of HGSC.

Background: Neurogenic tumors are rare but represent an important consideration in the differential diagnosis of abdominal mesenchymal tumors. Reports on their incidence, pathological features and clinical characteristics are scarce., Aim: To advance the overall knowledge on the histologic, immunohistochemical, clinical and radiologic characteristics of neurogenic tumors through this case series., Methods: An established database of a nationwide tertiary referral center, covering a 15-year period (2005 and 2020), was retrospectively re-evaluated. Diagnoses of neurogenic tumor cases were confirmed by two experts following review of the macroscopic, histological and immunohistochemical records along with findings from analysis of archived tissue sections for each included patient. Tissue microarrays were constructed for cases lacking necessary immunohistochemical studies. Clinical data and follow-up information were collected from the hospital records and the patients themselves, when available., Results: The study included 19 cases of intraabdominal neurogenic tumors, representing 12 women and 7 men, between 18 and 86 years of age (median: 51 years). Final confirmed diagnoses were 12 schwannomas, 2 diffuse submucosal neuro-fibromatoses, 2 ganglioneuromas, 2 malignant peripheral sheath nerve tumors, and 1 mucosal Schwann cell hamartoma. Sizes of the tumors were variable, with a median diameter of 4 cm; the two largest (> 10 cm) were schwannomas. The majority of cases were asymptomatic at presentation, but the most frequent symptom was abdominal pain. Gastrointestinal tract lesions were detected with endoscopy and extra-luminal lesions were detected with cross-sectional imaging. All cases were S100-positive and CD117-negative; most cases were negative for desmin, epithelial membrane antigen, smooth muscle actin and CD34. In all but 5 cases, the Ki67 proliferation index was ≤ 1%., Conclusion: Re-evaluation of 19 cases of abdominal neurogenic tumors demonstrated con-siderable variability in clinicopathologic characteristics depending on location, dimension and histological features., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest, either real or perceived, in relation to this study., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Human breast milk offers the optimal nutrition for all infants and have been widely used in biomonitoring programs to assess human exposure to lipophylic environmental contaminants such as polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF) and polychlorinated biphenyls (PCB). There are no previous reports from Turkey on chemically determined levels of PCDDs, PCDFs, and PCBs in human breast milk expressed as World Health Organization (WHO) toxic equivalents (TEQ). To get an overview of the levels of these contaminants in Turkish human milk, samples from 51 Turkish women living in the Ankara, Istanbul, Antalya, Kahramanmaraş, and Afyon provinces were analyzed by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) throughout 2007. The mean concentrations of WHO(PCDD/F-)TEQ and WHO(PCB-)TEQ of all samples from the five regions were 7.5 and 3.1 pg g(-1) on a lipid basis, respectively. PCDD/F concentrations ranged between 0.78 and 29.3 pg WHO-TEQ g(-1) fat (1.7 and 36.2 pg WHO-TEQ g(-1) fat, respectively, including PCB). Of the five studied locations, the lowest levels of sigmaTEQs (PCDD/F+PCB) were found in the Afyon (6.8 pg WHO-TEQ g(-1) fat) and the highest in the Antalya (15.6 pg WHO-TEQ g(-1) fat) province. The results have been discussed in terms of regions and PCDD/F and PCBs for which analyses had been made. The mean levels of PCDD/Fs and PCBs in Turkish human milk are comparable to that found in other countries.

Solid lipid nanoparticles (SLN) have been reported to be an alternative system to emulsions, liposomes, microparticles and their polymeric counterparts for various application routes since the early 1990s due to their advantages. Various research groups have also increasingly focused on improving their stability in body fluids after administration by coating of particles with hydrophilic molecules such as poly(ethylene)glycol (PEG) derivatives. Altering surface characteristics by coating SLN with hydrophilic molecules improves plasma stability and biodistribution, and subsequent bioavailability of drugs entrapped. Their storage stability is also increased. This paper basicly reviews types of SLN, principles of drug loading and models of drug incorporation. The influence of PEG coating on particle size and surface characteristics is discussed followed by alteration in pharmacokinetics and bioavailability of drugs in order to target the site of action via SLN. The future direction of research and clinical implications of SLN is also considered.

Opipramol 2-HCl (OP) is used for therapy of general somatoform and anxiety disorders. Conventional tablets in the market contain 50 mg OP to be used once or up to three times a day in effective treatment of depression in mild. In case of serious depressive disorders, OP may be administired up to 300 mg a day. Decrease in frequency of high dose administration via sustained drug release would reduce incidence of symptoms of intoxication in long-term use of OP. With this aim, OP matrix tablets containing 100 mg were prepared by direct compression method to be used once a day to provide patient compliance and constant blood level, consequently to decrease side effects. Two concentrations of polymers (10% and 20%): hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), sodium alginate (NaAlg), xanthan gum (XG) and Carbopol(®)941 (C941) were used in preparation of matrix tablets. Drug release study were performed in distilled water, pH1.2 HCl buffer and pH7.4 phosphate buffer solutions according to the Method II in USP 29. Two commercial tablets containing 50 mg OP available in Turkish market were used for comparison. Kinetic models of release patterns from tablets were evaluated. Drug release was displayed slower to faster pattern in order of formulations containing C941, HPMC and HPC. Drug release was significantly faster in tablets of 10% polymers than those of 20%. NaAlg and XG were insufficient to sustain drug release. The most sustaining drug release effect at the lowest polymer concentration was obtained with C941. Drug release from matrix tablets containing 10% C941 was determined as 58.2%, 52.4 and 57.0% in related dissolution mediums above after 8 hours, respectively. However, HPMC and HPC sustained drug release at 20% concentration. As a result, Carbopol® 941, HPMC and HPC can be suggested as suitable to prepare matrix tablets of OP.

Objective: To evaluate the efficiency of radionuclide hysterosalpingography (HSG) by using 99mTc hexamethyl propyleneamine oxime (HMPAO)-labeled human spermatozoa in the assessment of fallopian tube patency in infertile couples., Design: Fifteen infertile female patients were inseminated with their husbands' radiolabeled spermatozoa immediately after cessation of menses., Setting: University-based academic hospital., Main Outcome Measure(s): The time course of radioactivity and scintigraphic images of the uterus and the parauterine tissues implying tubal patency were evaluated and compared by using laparoscopy and HSG., Result(s): We demonstrated Tmax (time to peak radioactivity at periovarian sites) for right and left tubes to be 6.74 +/- 2.66 and 5.91 +/- 2.93 minutes (means +/- SD), respectively. We also found 72% sensitivity and 75% specificity of spermatozoa labeled radionuclide HSG compared with laparoscopic findings for tubal patency., Conclusion(s): Radionuclide HSG with the husband's spermatozoa seems to be a potentially useful method of assessing patency of the fallopian tubes. The safety dose of this procedure is comparable to conventional HSG. However, more comparative studies are needed to evaluate advantages and disadvantages of this technique.

This paper presents a female patient with clinical features of Turner's Syndrome and the chromosomal constitution of 45,X/46,X,dic (X) (qter----p11.1::p11.4----qter). This abnormal X chromosome was compared with similar-structured dic(X).