Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.

• MeSH
• buňky NK imunologie   účinky léků   metabolismus   MeSH
• dithiokarb * farmakologie   MeSH
• kolorektální nádory * farmakoterapie   imunologie   metabolismus   patologie   MeSH
• lektinové receptory NK-buněk - podrodina K * metabolismus   MeSH
• lidé MeSH
• měď MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * účinky léků   imunologie   MeSH
• protinádorové látky farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In recent years, the dynamics and function of cross-frequency coupling (CFC) in electroencephalography (EEG) have emerged as a prevalent area of investigation within the research community. One possible approach in studying CFC is to utilize non-invasive neuromodulation methods such as transcranial alternating current stimulation (tACS) and neurofeedback (NFB). In this study, we address (1) the potential applicability of single and multifrequency tACS and NFB protocols in CFC research; (2) the prevalence of CFC types, such as phase-amplitude or amplitude-amplitude CFC, in tACS and NFB studies; and (3) factors that contribute to inter- and intraindividual variability in CFC and ways to address them potentially. Here we analyzed research studies on CFC, tACS, and neurofeedback. Based on current knowledge, CFC types have been reported in tACS and NFB studies. We hypothesize that direct and indirect effects of tACS and neurofeedback can induce CFC. Several variability factors such as health status, age, fatigue, personality traits, and eyes-closed (EC) vs. eyes-open (EO)condition may influence the CFC types. Modifying the duration of the tACS and neurofeedback intervention and selecting a specific demographic experimental group could reduce these sources of CFC variability. Neurofeedback and tACS appear to be promising tools for studying CFC.

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Despite a growing body of research on pornography use among women, there is a lack of understanding of the problematic versus non-problematic nature. The current study aimed to investigate the relationship between women's motivations for pornography use and sexual wellbeing using a cross-sectional, self-report survey design among participants from 42 countries. METHODS: The total sample included 82,243 participants, of whom 46,874 (57.0%) identified as women and were analyzed. The participants' age averaged at M = 29.67 years, with a standard deviation of SD = 10.11. Participants were asked to complete a questionnaire assessing their motivations for pornography use, as well as measures of sexual functioning, sexual desire, and sexual satisfaction. RESULTS: Study results suggest that across cultures, women's motivations for pornography use are associated with their sexual wellbeing. Specifically, when women reported using pornography for their own pleasure or sexual curiosity, it was associated with fewer sexual functioning problems and higher sexual desire. Conversely, when women reported using pornography due to a lack of sexual satisfaction in their relationships, it was associated with more sexual functioning problems. DISCUSSION AND CONCLUSIONS: These findings highlight the need to consider the multifaceted nature of pornography use among women, including the usage motives, to fully understand associations with sexual wellbeing. Additionally, the study emphasizes the importance of conducting further research utilizing longitudinal designs, to establish the directionality between pornography use motivations and sexual wellbeing among women.

• MeSH
• dospělí MeSH
• erotika * psychologie   MeSH
• libido fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• motivace * MeSH
• osobní uspokojení MeSH
• průřezové studie MeSH
• sexuální chování * psychologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Coriolus versicolor (CV), known in traditional Chinese medicine for over 2000 years, is currently used in China and Japan to reduce chemotherapy or radiotherapy side effects in cancer patients. Despite extensive research, its effects still need improvement. This study aimed to determine if combining CV extract with LY294002, an inhibitor of the phosphatidylinositol-3-kinase (PI3K) signalling pathway, enhances cancer cell treatment, potentially leading to a novel therapeutic approach. Three human cancer cell lines (MCF-7, HeLa, and A549) were treated with CV extract alone or combined with LY294002. Cell viability was assessed using MTT assays. Then, HeLa and MCF-7 cells most sensitive to the co-treatment were used to evaluate colony formation, apoptosis, cell cycle, cell migration and invasion, and phospho-PI3K expression. The results demonstrated that LY294002 enhanced the CV extract's anti-tumour effects by reducing cell viability and colony formation. The combined treatment with CV extract and LY294002 more effectively induced G0/G1 cell cycle arrest, promoted apoptosis, reduced cell invasion and migration, and inhibited phospho-PI3K expression compared to each agent alone. This study highlights the potent cytotoxic enhancement between CV extract and LY294002 on cancer cells, primarily by inhibiting phospho-PI3K expression. These findings suggest promising avenues for developing novel combination therapies targeting cancer.

• MeSH
• apoptóza * účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• buňky A549 MeSH
• chromony * farmakologie   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• HeLa buňky MeSH
• inhibitory fosfoinositid-3-kinasy * farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• morfoliny * farmakologie   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk * účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• rostlinné extrakty farmakologie   chemie   MeSH
• signální transdukce účinky léků   MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The medial approach for minimally invasive harvesting of a deep circumflex iliac artery (DCIA) flap is described for reconstruction of the jaw. The associated preservation of the crest of the ilium prevents the raising of the abdominal internal oblique muscle (IO) in a standard fashion. However, reconstructive surgery of composite mandibular defects includes bone and soft tissue. To achieve this goal, we combined this technique with a new perforator-based raising of the IO for reconstruction of intraoral soft tissue. METHODS: In this study, we present eight cases of patients with composite mandibular defects who underwent the myo-osseous DCIA flap procedure with an IO perforator. Virtual surgical planning was employed to preplan the size and configuration of the graft. Cutting guides were made using CAD/CAM technology. The surgical procedure followed the described medial approach for minimally invasive harvesting, leaving the iliac crest, spine, and skin intact. In addition, we completely cut and isolated the IO with its sole attachment being the ascending branch of the DCIA. We used either a surgical guide with a slot to lead through both the transverse branch of the bone and the ascending branch of the IO or a surgical guide consisting of 2 parts. RESULTS: In all instances, the flap successfully survived with a 100% success rate. There were no signs of infection, wound opening, or bleeding in either patient. Furthermore, the patients did not exhibit permanent complications related to the donor site. The internal oblique perforator flap exhibited remarkable integration in all patients and underwent rapid transformation. Notably, the flap developed keratinized mucosa (KM) that closely resembled the attached gingiva. CONCLUSION: Our study demonstrated the effectiveness of a medial approach for harvesting a newly designed more flexible chimeric myo-osseous deep circumflex iliac artery flap. By incorporating virtual surgical planning and custom-made cutting guides for obtaining deep circumflex iliac artery flaps through the medial route along with an internal oblique perforator flap, we have established a highly promising method for the rehabilitation of patients with composite mandibular defects. This approach not only improves functional outcomes, but also enhances aesthetic results to maintain patients' quality of life.

• MeSH
• arteria iliaca chirurgie   MeSH
• chirurgické laloky MeSH
• design s pomocí počítače MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mandibula chirurgie   MeSH
• miniinvazivní chirurgické výkony metody   MeSH
• os ilium chirurgie   MeSH
• senioři MeSH
• zákroky plastické chirurgie * metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PSMA-617 is recognized as a benchmark ligand for prostate-specific membrane antigen (PSMA) owing to its broad utilization in prostate cancer (PCa) targeted radionuclide therapy. In this study, the structure-activity relationships (SAR) of PSMA-617 and two novel analogs featuring modified linkers were investigated. In compounds P17 and P18, the 2-naphthyl-l-Ala moiety was replaced with a less lipophilic 3-styryl-l-Ala moiety while the cyclohexyl ring in P18 was replaced with a phenyl group. The first ever crystal structure of the PSMA/PSMA-617 complex reported here revealed a folded conformation of the PSMA-617 linker while for the PSMA/P17 and PSMA/P18 complexes, the extended orientations of the linkers revealed linker flexibility within the PSMA cavity, a change in binding that can be exploited for the structure-guided design of PSMA-targeting agents. Despite structural differences from PSMA-617, the analogs maintained high PSMA inhibition potency, cellular binding, and internalization. In vivo biodistribution studies revealed comparable tumor uptake across all three compounds with P18 displaying higher spleen accumulation, likely due to phenyl ring lipophilicity. These SAR findings provide a strategic framework for the rational design of PSMA ligands, paving the way for the development of next-generation theranostic agents for PCa.

• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Problematic online video pornography consumption is associated with sexual objectification, particularly in male consumers. However, previous studies have not considered that there is a subgroup of internet users whose consumption may become problematic due to their internet sex addiction. Such users may, in response to internet sex addiction symptoms such as craving, have increased levels of sexual objectification. METHODS: In a sample of 1,272 male consumers of online video pornography (Mage = 32.93, SDage = 9.44), we examined whether internet sex addiction is linked to sexual objectification via an online survey. RESULTS: We fitted a series of structural equation models and found that men who scored higher on internet sex addiction were more likely to objectify women. More importantly, this link did not cease when controlling for the frequency of online video pornography consumption. DISCUSSION: Our findings suggest that there are other mechanisms related to addictive symptomatology than just the link through online video pornography consumption that may contribute to sexual objectification. Addiction-related factors may have a unique role in fostering sexual objectification. Isolating internet sex addiction as a potential driver highlights the need to address objectifying behaviours in individuals struggling with this addiction.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: The decrease in the number of healthcare workers and the resulting deterioration in healthcare quality and availability have been subjected to intensive discussion in Czechia in recent years. Estimating future healthcare worker capacities requires a detailed analysis of their "movement" within the healthcare system. This study focuses on exits of the primary care physicians from the healthcare system in Czechia. METHODS: Using anonymised data obtained from the largest Czech health insurance company (2012-2022), we constructed working life tables and calculated working life expectancy, which indicates the expected average number of remaining years of work at the exact age of the physician. The study focuses on primary care physicians, who are crucial for the effective functioning of the healthcare system. RESULTS: At age 50, working life expectancy was 20 years for female physicians and approximately 21 years for male physicians. Over the monitored period, working life expectancy decreased by 1 year for both genders. Gynaecologists had the longest working life expectancy, while dentists had the shortest. CONCLUSIONS: The decrease in the working life expectancy and the length of tenure indicates the need to create favourable conditions for the extension of the working lives of physicians to avoid early exits from the system.

• MeSH
• dospělí MeSH
• lékaři primární péče * MeSH
• lidé středního věku MeSH
• lidé MeSH
• naděje dožití * MeSH
• primární zdravotní péče MeSH
• zaměstnanost statistika a číselné údaje   MeSH
• zubní lékaři statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Maternal perinatal mental health is essential for optimal brain development and mental health of the offspring. We evaluated whether maternal depression during the perinatal period and early life of the offspring might be selectively associated with altered brain function during emotion regulation and whether those may further correlate with physiological responses and the typical use of emotion regulation strategies. METHODS: Participants included 163 young adults (49% female, 28-30 years) from the ELSPAC prenatal birth cohort who took part in its neuroimaging follow-up and had complete mental health data from the perinatal period and early life. Maternal depressive symptoms were measured mid-pregnancy, 2 weeks, 6 months, and 18 months after birth. Regulation of negative affect was studied using functional magnetic resonance imaging, concurrent skin conductance response (SCR) and heart rate variability (HRV), and assessment of typical emotion regulation strategy. RESULTS: Maternal depression 2 weeks after birth interacted with sex and showed a relationship with greater brain response during emotion regulation in a right frontal cluster in women. Moreover, this brain response mediated the relationship between greater maternal depression 2 weeks after birth and greater suppression of emotions in young adult women (ab = 0.11, SE = 0.05, 95% CI [0.016; 0.226]). The altered brain response during emotion regulation and the typical emotion regulation strategy were also as sociated with SCR and HRV. CONCLUSIONS: These findings suggest that maternal depression 2 weeks after birth predisposes female offspring to maladaptive emotion regulation skills and particularly to emotion suppression in young adulthood.

• MeSH
• deprese patofyziologie   diagnostické zobrazování   MeSH
• dospělí MeSH
• emoční regulace * fyziologie   MeSH
• galvanická kožní odpověď fyziologie   MeSH
• kohortové studie MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• matky psychologie   MeSH
• mozek diagnostické zobrazování   patofyziologie   MeSH
• srdeční frekvence fyziologie   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs). METHODS: We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs. RESULTS: Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy. CONCLUSIONS: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.

• MeSH
• adipogeneze * účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• hypoglykemika farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• metabolomika MeSH
• mezenchymální kmenové buňky * účinky léků   metabolismus   MeSH
• osteogeneze * účinky léků   MeSH
• pioglitazon farmakologie   MeSH
• rosiglitazon farmakologie   MeSH
• thiazolidindiony * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH