Association between Toll-like receptor 2 rs4696483 and rs1898830 polymorphisms and the risk of triple-negative breast cancer.

PURPOSE: Breast cancer (BC) is heterogeneous in clinical manifestation, of which the triple-negative (TNBC) subtype is the most aggressive. This study examines the associations between Toll-Like Receptor (TLR)-2 polymorphisms and the susceptibility to BC and TNBC. METHODS: Genotyping of TLR-2 rs1898830 and rs4696483 polymorphisms was done by real-time PCR in 488 women with BC (130 TNBC, 358 non-TNBC) and 476 cancer-free control women. RESULTS: The minor allele frequency (MAF) of rs4696483 was significantly lower in BC cases compared to controls, and significantly lower frequencies of rs4696483 C/T and higher frequencies of rs1898830 G/G genotypes were seen in BC cases. Significantly higher MAF of rs4696483 and higher C/T and T/T rs4696483 genotypes frequencies were seen in TNBC than in non-TNBC cases. Considering the prevalent AC haplotype as a reference, 2-locus TLR-2 haplotype analysis did not identify any 2-locus TLR-2 haplotype associated with an altered risk of BC or TNBC. Positive associations of rs1898830 and rs4966483 were seen with the histological type in TNBC and negatively with distant metastasis and HR status in TNBC and non-TNBC rs1898830 carriers. In addition, rs4696483 was positively correlated with hormonotherapy and surgery in non-TNBC cases, while rs1898830 was negatively associated with hormonotherapy. Furthermore, rs1898830 was negatively and positively correlated with BMI in TNBC and TNBC cases, respectively, but positively with Ki-67 status. CONCLUSIONS: Our study highlights the association between TLR-2 genetic polymorphisms and BC and TNBC susceptibility, suggesting these variants' diagnostic/prognostic capacity in BC patients and patient subgroups.

All organic nanomedicine for PDT-PTT combination therapy of cancer cells in hypoxia.

Photodynamic and photothermal therapies are promising treatments for cancer, dermatological, and ophthalmological conditions. However, photodynamic therapy (PDT) is less effective in oxygen-deficient tumor environments. Combining PDT with photothermal therapy (PTT) can enhance oxygen supply and treatment efficacy. Inorganic PTT agents pose toxicity risks, limiting their clinical use despite their high performance. In this study, we developed a novel nanomedicine integrating an all-organic photothermal agent and an organic photosensitizer, creating a colocalized nanoplatform to enhance phototherapy efficacy in cancer treatment. PTT nanoparticles (NPs) were synthesized through a thermal phase transition of organic chromophores, demonstrating superior photothermal properties and photostability. Utilizing this nanoplatform, we devised 'Combi NPs' for combined PDT-PTT nanomedicine. Tests on A549 cancer cell lines have revealed that Combi NPs exhibit superior cytotoxicity and induce apoptosis in hypoxic conditions, outperforming PTT-only NPs. The all-organic Combi NPs show significant potential for clinical cancer phototherapy in hypoxic microenvironments, potentially mitigating long-term nanomedicine accumulation and associated toxicity.

A hybrid fluorescent nanofiber membrane integrated with microfluidic chips towards lung-on-a-chip applications.

Here, we report a fluorescent electrospun nanofiber membrane for integration into microfluidic devices towards lung-on-a-chip applications complemented with the results of computational fluid dynamics modelling. A proposed hybrid poly(ε-caprolactone) (PCL)-collagen membrane was developed, characterized, tested, and integrated into a prototype microfluidic chip for biocompatibility studies. The resulting membrane has a thickness of approximately 10 µm, can be adjusted for appropriate porosity, and offers excellent biocompatibility for mimicry of a basement membrane to be used in lung-on-a-chip device applications. Several membrane variations were synthesized and evaluated using SEM, FTIR, AFM, and high-resolution confocal fluorescence microscopy. A sample microfluidic chip made of cyclic olefin copolymer and polydimethylsiloxane was built and integrated with the developed PCL-collagen membrane for on-chip cell culture visualisation and biocompatibility studies. The sample chip design was modelled to determine the optimal fluidic conditions for using the membrane in the chip under fluidic conditions for future studies. The integration of the proposed membrane into microfluidic devices represents a novel strategy for improving lung-on-a-chip applications which can enhance laboratory recapitulation of the lung microenvironment.

Recurrent Pregnancy Loss Etiology, Risk Factors, Diagnosis, and Management. Fresh Look into a Full Box.

Recurrent pregnancy loss is a complex health challenge with no universally accepted definition. Inconsistency in definitions involves not only the number of spontaneous abortions (two or three) that are accepted for recurrent pregnancy loss but the types of pregnancy and gestational age at miscarriage. Due to the heterogeneity of definitions and criteria applied by international guidelines for recurrent pregnancy loss, the true incidence of recurrent miscarriage, which is reported to range from 1% to 5%, is difficult to estimate. Moreover, the exact etiology of recurrent pregnancy loss remains questionable; thus, it is considered a polyetiological and multifactorial condition with many modifiable and non-modifiable factors involved. Even after thoroughly evaluating recurrent pregnancy loss etiology and risk factors, up to 75% of cases remain unexplained. This review aimed to summarize and critically analyze accumulated knowledge on the etiology, risk factors, relevant diagnostic options, and management approach to recurrent pregnancy loss. The relevance of various factors and their proposed roles in recurrent pregnancy loss pathogenesis remains a matter of discussion. The diagnostic approach and the management largely depend on the etiology and risk factors taken into consideration by a healthcare professional as a cause of recurrent miscarriage for a particular woman or couple. Underestimation of social and health consequences of recurrent pregnancy loss leads to compromised reproductive health and psychological well-being of women after miscarriage. Studies on etiology and risk factors for recurrent pregnancy loss, especially idiopathic, should be continued. The existing international guidelines require updates to assist clinical practice.

Relation of CRP gene variants to altered risk of Helicobacter pylori - associated chronic gastritis: A case-control study in Tunisia.

BACKGROUND: We investigated the association between CRP variants and chronic gastritis in H. pylori-infected patients at the allele, genotype, and haplotype levels. This was also assessed according to serum hs-CRP levels. METHODS: Study subjects consisted of 77 H. pylori-infected patients and 96 H. pylori-negative controls. Genotyping of the CRP rs1572970, rs876537, rs2794520, rs2808630, rs1130864, rs1417938, rs7553007, and rs4285692 variants were analyzed by real-time PCR. RESULTS: Significantly higher MAF and increased risk of chronic gastritis were associated with rs1130864, rs1417938, and rs7553007, which persisted after controlling for key covariates. Significant differences in the genotype distribution of rs1130864, rs1417938, and rs7553007 were also seen between H. pylori-infected patients and healthy controls. Increased risk of H. pylori-associated chronic gastritis was associated with carriage of rs1130864 C/T, and more with T/T genotype carriers, as well as with rs1417938 T/A and A/A genotype carriers. Functionally, the distribution of rs1130864 and rs1417938 genotypes were significantly different between H. pylori-infected patients and controls in the low hs-CRP (<6 mg/L) group. CRP haplotype analysis identified Block 1 (rs1572970, rs876537, rs2794520), and Block 2 (rs2808630, rs1130864, rs1417938) associated with H. pylori infection. Haplotypes ACC (Block 1) and TTA and TTT (Block 2) were positively associated with H. pylori-associated chronic gastritis with low hs-CRP levels. CONCLUSION: Altered serum levels of hs-CRP, stemming in part from the presence of specific genetic variants in CRP gene, modulate the risk of H. pylori infection.

Human forkhead box protein 3 gene variants associated with altered susceptibility to idiopathic recurrent pregnancy loss: A retrospective case-control study.

BACKGROUND: The pathogenesis of recurrent pregnancy loss (RPL) is multifactorial and not completely elucidated. Dysregulated immunity was implicated with RPL, in which regulatory T cells (Tregs) are key. As Tregs development and function are regulated by forkhead box P3 (FOXP3) transcription factor, and as FOXP3 expression is genetically determined, a role for FOXP3 polymorphisms in RPL pathogenesis was suggested. AIM: To investigate the association of rs2294021, rs2232365, rs3761548, and rs141704699 FOXP3 variants with idiopathic RPL in Lebanese women. METHODS: This retrospective case-control study included 386 RPL cases and 398 age-matched control women. Logistic odds ratios (OR) were estimated with 95% confidence interval after adjustment; a significance value of P<.05 was set. RESULTS: Significantly lower rs22944021 and rs2232365 minor allele frequency (MAF) was found in patients with idiopathic RPL in comparison with the control group. Furthermore, statistically significantly lower frequency of heterozygous and homozygous rs2294021 and rs2232365 genotypes was seen in controls, while significantly lower rs3761548 heterozygous genotype frequencies were found in the patient group. Obesity, antihypertension treatment, smoking, positive RPL family history, abortion state, and infertility treatment correlated negatively with rs2294021, while rs2232365 negatively correlated with obesity, and rs3761548 negatively correlated with infertility treatment. Marked linkage disequilibrium (LD) was noted among FOXP3 SNPs, with TGCC and CGAC haplotypes being positive, while CAAC, CACC, and TGAC haplotypes being negatively associated with RPL risk. Except for CGAC, the association of these haplotypes with RPL persisted after adjustment. CONCLUSION: FOXP3 gene variants and haplotypes are associated with altered incidence of RPL, proposing the role of Treg in RPL pathogenesis.

Microfluidic Organ-on-a-Chip Devices for Liver Disease Modeling In Vitro.

Mortality from liver disease conditions continues to be very high. As liver diseases manifest and progress silently, prompt measures after diagnosis are essential in the treatment of these conditions. Microfluidic organs-on-chip platforms have significant potential for the study of the pathophysiology of liver diseases in vitro. Different liver-on-a-chip microphysiological platforms have been reported to study cell-signaling pathways such as those activating stellate cells within liver diseases. Moreover, the drug efficacy for liver conditions might be evaluated on a cellular metabolic level. Here, we present a comprehensive review of microphysiological platforms used for modelling liver diseases. First, we briefly introduce the concept and importance of organs-on-a-chip in studying liver diseases in vitro, reflecting on existing reviews of healthy liver-on-a-chip platforms. Second, the techniques of cell cultures used in the microfluidic devices, including 2D, 3D, and spheroid cells, are explained. Next, the types of liver diseases (NAFLD, ALD, hepatitis infections, and drug injury) on-chip are explained for a further comprehensive overview of the design and methods of developing liver diseases in vitro. Finally, some challenges in design and existing solutions to them are reviewed.

Genetic variation in progesterone receptor gene and ovarian cancer risk: A case control study.

BACKGROUND: Previous studies examined the association of genetic variation in progesterone receptor (PR) gene (PGR) with ovarian cancer, possibly by altering the expression of PR-B isoform, but with mixed outcome. OBJECTIVE: This study evaluated the association of PGR variants with ovarian cancer and associated features. METHODS: This was a retrospective case-control study, which involved 82 women with ovarian cancer and 95 cancer-free women who served as controls. Genotyping was done by Taqman® SNP genotyping by qRT-PCR. The PGR variants tested were rs471767 (A > G), rs590688 (G > C), and rs10895068 (G > A). Stratification analyses were used for testing the correlation between the PGR variants with ovarian cancer susceptibility according to menstruation status, FIGO classification, pathological grade, and chemotherapy. RESULTS: Significantly lower minor allele frequency (MAF) of rs10895068 was seen among ovarian cancer patients, thereby imparting disease protective nature to this variant. Significant association of rs10895068 genotypes with ovarian cancer was seen under the dominant model, but not other genetic models. FIGO classification correlated positively with rs471767 and rs10895068, while rs10895068 correlated positively with lymph node positivity. Three-locus haplotype analysis identified ACA and HCG haplotypes to be negatively associated with the risk of ovarian cancer. CONCLUSIONS: This report confirms the contribution of PGR variants, specifically the rs10895068 (+331G/A) the etiology of ovarian cancer.

Association of Human forkhead box protein 3 (FOXP3) gene polymorphisms with idiopathic recurrent pregnancy loss among Kazakhstani women.

BACKGROUND: Recurrent pregnancy loss (RPL) is major pregnancy complication, with poorly defined cause.Forkhead Box P3 (FOXP3) is a transcription factor that supports Treg activation and development and attenuates immune responses. As FOXP3 production is genetically determined, we tested the association of FOXP3 gene variants with RPL. METHODS: A retrospective case-control study, performed between April 2019 and February 2020. Study subjects comprised 62 RPL cases and 60 control women. Genotyping of the four FOXP3 variants rs2294021 (T > C), rs2232365 (G > A), rs3761548 (C > A), and rs141704699 (C > T) was done by real-time PCR, with defined clusters. Logistic odds ratios (ORs) of RPL risk were estimated with 95% confidence interval (CI) after adjustment; statistical significance set at P < 0.05. RESULTS: Minor allele frequency (MAF) of rs2294021 was significantly lower [P < 0.001; OR(95% CI) = 0.25(0.11-0.55)], while rs2232365 MAF was significantly higher [P = 0.045; OR(95% CI) = 1.85(1.05-3.28)] in cases, hence assigning RPL-protection and -susceptibility to these variants, respectively. Increased RPL risk was seen in rs2232365 homozygous minor allele carrying genotype [OR(95% CI) = 5.14(1.01-26.15)], while reduced RPL risk was noted in rs2294021 heterozygous [OR(95% CI) = 0.30(0.11-0.80)], and homozygous minor allele [OR(95% CI) = 0.10(0.01-0.83)] genotype carriers. Moderate linkage disequilibrium analysis was seen between the tested variants. Increased frequency of TACC, and reduced frequency of CGAC haplotypes were seen in RPL cases when compared to controls, thereby assigning RPL susceptibility and protection to these haplotypes, respectively. CONCLUSION: These results suggest that FOXP3 variants and haplotypes are associated with idiopathic RPL, suggesting the likely contribution of Treg to RPL.