Different machine learning methods based on maxillary sinus in sex estimation for northwestern Chinese Han population.

BACKGROUND & OBJECTIVE: Sex estimation is a critical aspect of forensic expertise. Some special anatomical structures, such as the maxillary sinus, can still maintain integrity in harsh environmental conditions and may be served as a basis for sex estimation. Due to the complex nature of sex estimation, several studies have been conducted using different machine learning algorithms to improve the accuracy of sex prediction from anatomical measurements. MATERIAL & METHODS: In this study, linear data of the maxillary sinus in the population of northwest China by using Cone-Beam Computed Tomography (CBCT) were collected and utilized to develop logistic, K-Nearest Neighbor (KNN), Support Vector Machine (SVM) and random forest (RF) models for sex estimation with R 4.3.1. CBCT images from 477 samples of Han population (75 males and 81 females, aged 5-17 years; 162 males and 159 females, aged 18-72) were used to establish and verify the model. Length (MSL), width (MSW), height (MSH) of both the left and right maxillary sinuses and distance of lateral wall between two maxillary sinuses (distance) were measured. 80% of the data were randomly picked as the training set and others were testing set. Besides, these samples were grouped by age bracket and fitted models as an attempt. RESULTS: Overall, the accuracy of the sex estimation for individuals over 18 years old on the testing set was 77.78%, with a slightly higher accuracy rate for males at 78.12% compared to females at 77.42%. However, accuracy of sex estimation for individuals under 18 was challenging. In comparison to logistic, KNN and SVM, RF exhibited higher accuracy rates. Moreover, incorporating age as a variable improved the accuracy of sex estimation, particularly in the 18-27 age group, where the accuracy rate increased to 88.46%. Meanwhile, all variables showed a linear correlation with age. CONCLUSION: The linear measurements of the maxillary sinus could be a valuable tool for sex estimation in individuals aged 18 and over. A robust RF model has been developed for sex estimation within the Han population residing in the northwestern region of China. The accuracy of sex estimation could be higher when age is used as a predictive variable.

Sex estimation using maxillary sinus volume for Chinese subjects based on cone-beam computed tomography.

BACKGROUND: Sex estimate is a key stage in forensic science for identifying individuals. Some anatomical structures may be useful for sex estimation since they retain their integrity even after highly severe events. However, few studies are focusing on the Chinese population. Some researchers used teeth for sex estimation, but comparison with maxillary sinus were lack. As a result, the objective of this research is to develop a sex estimation formula for the northwestern Chinese population by the volume of the maxillary sinus and compare with the accuracy of sex estimation based on teeth through cone-beam computed tomography (CBCT). METHODS: CBCT images from 349 samples were used to establish and verify the formula. The volume of both the left and right maxillary sinuses was measured and examined for appropriate formula coefficients. To create the formula, we randomly picked 80% of the data as the training set and 20% of the samples as the testing set. Another set of samples, including 20 males and 20 females, were used to compare the accuracy of maxillary sinuses and teeth. RESULTS: Overall, sex estimation accuracy by volume of the left maxillary sinus can reach 78.57%, while by the volume of the right maxillary sinus can reach 74.29%. The accuracy for females, which can reach 91.43% using the left maxillary sinus, was significantly higher than that for males, which was 65.71%. The result also shows that maxillary sinus volume was higher in males. The comparison with the available results using measurements of teeth for sex estimation performed by our group showed that the accuracy of sex estimation using canines volume was higher than the one using maxillary sinus volume, the accuracies based on mesiodistal diameter of canine and first molar were the same or lower than the volume of maxillary sinus. CONCLUSIONS: The study demonstrates that measurement of maxillary sinus volume based on CBCT scans was an available and alternative method for sex estimation. And we established a method to accurately assess the sex of the northwest Chinese population. The comparison with the results of teeth measurements made the conclusion more reliable.

Dental Age Estimation in Northern Chinese Han Children and Adolescents Using Demirjian's Method Combined with Machine Learning Algorithms.

OBJECTIVES: To investigate the application value of combining the Demirjian's method with machine learning algorithms for dental age estimation in northern Chinese Han children and adolescents. METHODS: Oral panoramic images of 10 256 Han individuals aged 5 to 24 years in northern China were collected. The development of eight permanent teeth in the left mandibular was classified into different stages using the Demirjian's method. Various machine learning algorithms, including support vector regression (SVR), gradient boosting regression (GBR), linear regression (LR), random forest regression (RFR), and decision tree regression (DTR) were employed. Age estimation models were constructed based on total, female, and male samples respectively using these algorithms. The fitting performance of different machine learning algorithms in these three groups was evaluated. RESULTS: SVR demonstrated superior estimation efficiency among all machine learning models in both total and female samples, while GBR showed the best performance in male samples. The mean absolute error (MAE) of the optimal age estimation model was 1.246 3, 1.281 8 and 1.153 8 years in the total, female and male samples, respectively. The optimal age estimation model exhibited varying levels of accuracy across different age ranges, which provided relatively accurate age estimations in individuals under 18 years old. CONCLUSIONS: The machine learning model developed in this study exhibits good age estimation efficiency in northern Chinese Han children and adolescents. However, its performance is not ideal when applied to adult population. To improve the accuracy in age estimation, the other variables can be considered.

New data on mitogenomes of Thienemanniella Kieffer, 1911 (Diptera: Chironomidae, Orthocladiinae).

The mitochondrial genome (mitogenome) has been widely used as a powerful marker in phylogenetic and evolutionary studies of various Dipteran groups. However, only a few mitogenomes from the Thienemanniella genus have been reported till now. Furthermore, there is still indeterminacy in the phylogenetic relationships of the genus Thienemanniella. In this study, mitogenomes of five Thienemanniella species were sequenced and analyzed newly. Combined with the published mitogenome of Thienemanniella nipponica, the obtained results showed that mitogenomes of Thienemanniella were conserved in structure, and all genes were observed to be arranged in the same gene order as the ancestral mitogenome. Nucleotide composition varied significantly among different genes, and the control region displayed the highest A + T content. All protein coding genes are subjected to purification selection, and the fastest evolving gene is ATP8. Maximum likelihood and Bayesian inference analyses showed the phylogeny of Thienemanniella which was supported in five topologies. Our present study provides valuable insight into the phylogenetic relationships of Thienemanniella species.

A non-randomized concurrent controlled trial of myofunctional treatment in the mixed dentition children with functional mouth breathing assessed by cephalometric radiographs and study models.

OBJECTIVES: This study aimed to examine the clinical effects of myofunctional treatment on children with functional mouth breathing by cephalometric radiographs and study models. METHODS: A total of 224 children (6-10 years old; 114 males and 110 females; SNA°: 82.24 ± 1.67°; ANB°: 2.79 ± 0.80°, 28° < SN-GoGn° < 37°) formed three groups: MB-M group (mouth breathers with myofunctional treatment,n = 75); MB-N group (mouth breathers with no treatment,n = 70); NB group (nasal breathers with no treatment, n = 79). A blind evaluation of cephalometric radiographs and study models was conducted at T1(pre-study) and T2 (post-study), respectively. RESULTS: Two hundred four children (MB-M:66, MB-N:68, NB:70) completed the present study. At T1, MB-M and MB-N groups, compared to their NB counterpart, had greater anterior lower facial height(P < 0.01) and overjet(P < 0.001) but shorter overbite and maxillary canines width (P < 0.001). At T2, the MB-N group exhibited a higher ANB angle, anterior lower facial height, and overjet, but shorter overbite and maxillary canines width (P < 0.001). From T1 to T2, the anterior lower facial height increased, overbite and the maxillary canines width further decreased in the MB-N group (P < 0.001). However, in the MB-M group, the incisors were retracted, overbite increased (P < 0.001), anterior lower facial height increased insignificantly (P > 0.05), and maxillary canines width increased slightly (P < 0.05). In the NB and MB-M groups, the mandible showed a normal tendency to grow forward, whereas, in the MB-N group, the mandible showed a tendency to grow downward (P < 0.001). CONCLUSIONS: Mouth breathers demonstrated increased anterior facial height and overjet but reduced overbite and maxillary arch width, which improved significantly following myofunctional treatment. TRIAL REGISTRATION: TCTR: TCTR20220401001 . Registered 1stApril 2022-Retrospectively registered.

Three-dimensional evaluation of pharyngeal airway and maxillary arch in mouth and nasal breathing children with skeletal Class I and II.

OBJECTIVE: This study aimed to investigate whether the subjects with mouth breathing (MB) or nasal breathing (NB) with different sagittal skeletal patterns showed different maxillary arch and pharyngeal airway characteristics. METHODS: Cone-beam computed tomography scans from 70 children aged 10 to 12 years with sagittal skeletal Classes I and II were used to measure the pharyngeal airway, maxillary width, palatal area, and height. The independent t-test and the Mann-Whitney U test were used for the intragroup analysis of pharyngeal airway and maxillary arch parameters. RESULTS: In the Skeletal Class I group, nasopharyngeal airway volume (P < 0.01), oropharyngeal airway volume (OPV), and total pharyngeal airway volume (TPV) (all P < 0.001) were significantly greater in subjects with NB than in those with MB. Furthermore, intermolar width, maxillary width at the molars, intercanine width, maxillary width at the canines, and palatal area were significantly larger in subjects with NB than in those with MB (all P < 0.001). In the Skeletal Class II group, OPV, TPV (both P < 0.05) were significantly greater in subjects with NB than in those with MB. No significant differences in pharyngeal airway parameters in the MB group between subjects with Skeletal Class I and those with Skeletal Class II. CONCLUSION: Regardless of sagittal Skeletal Class I or II, the pharyngeal airway and maxillary arch in children with MB differ from those with NB. However, the pharyngeal airway was not significantly different between Skeletal Class I and II in children with MB.

Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson's Disease via Inhibition of A1 Reactive Astrocytes.

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson's disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

Intraductal Injection of Lentivirus Vectors for Stably Introducing Genes into Rat Mammary Epithelial Cells in Vivo.

Various retroviral and lentiviral vectors have been used for up-the-teat intraductal injection to deliver markers, oncogenes, and other genes into mammary epithelial cells in mice. These methods along with the large number of genetically engineered mouse lines have greatly helped us learn normal breast development and tumorigenesis. Rats are also valuable models for studying human breast development and cancer. However, genetically engineered rats are still uncommon, and previous reports of intraductal injection of retroviral vectors into rats appear to be inefficient in generating mammary tumors. Here, we report, and describe the method for, stably introducing marker genes and oncogenes into mammary glands in rats using intraductal injection of commonly used lentiviral vectors. This method can infect mammary epithelial cells efficiently, and the infected cells can initiate tumorigenesis, including estrogen receptor-positive and hormone-dependent tumors, which are the most common subtype of human breast cancer but are yet still difficult to model in mice. This technique provides another tool for studying formation, prevention, and treatment of breast cancer, especially estrogen receptor-positive breast cancer.

Metformin improves depressive-like symptoms in mice via inhibition of peripheral and central NF-κB-NLRP3 inflammation activation.

Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Metformin has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. We used a chronic mild stress model of depression and cultured primary macrophage to investigate the effects of metformin on depression and its underlying mechanisms. We demonstrated that metformin alleviated depressive-like behaviors in the chronic mild stress-induced anhedonia model of depression. We further found that metformin significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1ß secretion in both peripheral macrophages and central hippocampus. Our findings reveal that metformin confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation. In light of metformin favorable properties, it should be evaluated in the treatment of depression and related neurologic disorders characterized by NLRP3 inflammasome activation.

EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis.

Many types of human tumor cells have overexpressed pyruvate kinase M2 (PKM2). However, the mechanism underlying this increased PKM2 expression remains to be defined. We demonstrate here that EGFR activation induces PLCγ1-dependent PKCε monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKCε interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCε phosphorylates IKKß at Ser177 and activates IKKß. Activated RelA interacts with HIF1α, which is required for RelA to bind the PKM promoter. PKCε- and NF-κB-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKKß activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-κB by EGF, in contrast to TNF-α, and the importance of the metabolic cooperation between the EGFR and NF-κB pathways in PKM2 upregulation and tumorigenesis.

Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice.

Twist1 is an epithelial-mesenchymal transition (EMT)-inducing transcription factor (TF) that promotes cell migration and invasion. To determine the intrinsic role of Twist1 in EMT and breast cancer initiation, growth, and metastasis, we developed mouse models with an oncogene-induced mammary tumor containing wild-type (WT) Twist1 or tumor cell-specific Twist1 knockout (Twist1TKO). Twist1 knockout showed no effects on tumor initiation and growth. In both models with early-stage tumor cells, Twist1, and mesenchymal markers were not expressed, and lung metastasis was absent. Twist1 expression was detected in ∼6% of the advanced WT tumor cells. Most of these Twist1+ cells coexpressed several other EMT-inducing TFs (Snail, Slug, Zeb2), lost ERα and luminal marker K8, acquired basal cell markers (K5, p63), and exhibited a partial EMT plasticity (E-cadherin+/vimentin+). In advanced Twist1TKO tumor cells, Twist1 knockout largely diminished the expression of the aforementioned EMT-inducing TFs and basal and mesenchymal markers, but maintained the expression of the luminal markers. Circulating tumor cells (CTCs) were commonly detected in mice with advanced WT tumors, but not in mice with advanced Twist1TKO tumors. Nearly all WT CTCs coexpressed Twist1 with other EMT-inducing TFs and both epithelial and mesenchymal markers. Mice with advanced WT tumors developed extensive lung metastasis consisting of luminal tumor cells with silenced Twist1 and mesenchymal marker expression. Mice with advanced Twist1TKO tumors developed very little lung metastasis. Therefore, Twist1 is required for the expression of other EMT-inducing TFs in a small subset of tumor cells. Together, they induce partial EMT, basal-like tumor progression, intravasation, and metastasis.

Evidence of Pure Spin-Current Generated by Spin Pumping in Interface-Localized States in Hybrid Metal-Silicon-Metal Vertical Structures.

Due to the difficulty of growing high-quality semiconductors on ferromagnetic metals, the study of spin diffusion transport in Si was limited to lateral geometry devices. In this work, by using an ultrahigh-vacuum wafer-bonding technique, we have successfully fabricated metal-semiconductor-metal CoFeB/MgO/Si/Pt vertical structures. We hereby demonstrate pure spin-current injection and transport in the perpendicular current flow geometry over a distance larger than 2 µm in n-type Si at room temperature. In those experiments, a pure propagating spin current is generated via ferromagnetic resonance spin pumping and converted into a measurable voltage by using the inverse spin Hall effect occurring in the top Pt layer. A systematic study varying both Si and MgO thicknesses reveals the important role played by the localized states at the MgO-Si interface for the spin-current generation. Proximity effects involving indirect exchange interactions between the ferromagnet and the MgO-Si interface states appears to be a prerequisite to establishing the necessary out-of-equilibrium spin population in Si under the spin-pumping action.

When did the ancestor of true bugs become stinky? Disentangling the phylogenomics of Hemiptera-Heteroptera.

The phylogeny of true bugs (Hemiptera: Heteroptera), one of the most diverse insect groups in terms of morphology and ecology, has been the focus of attention for decades with respect to several deep nodes between the suborders of Hemiptera and the infraorders of Heteroptera. Here, we assembled a phylogenomic data set of 53 taxa and 3102 orthologous genes to investigate the phylogeny of Hemiptera-Heteroptera, and both concatenation and coalescent methods were used. A binode-control approach for data filtering was introduced to reduce the incongruence between different genes, which can improve the performance of phylogenetic reconstruction. Both hypotheses (Coleorrhyncha + Heteroptera) and (Coleorrhyncha + Auchenorrhyncha) received support from various analyses, in which the former is more consistent with the morphological evidence. Based on a divergence time estimation performed on genes with a strong phylogenetic signal, the origin of true bugs was dated to 290-268 Ma in the Permian, the time in Earth's history with the highest concentration of atmospheric oxygen. During this time interval, at least 1007 apomorphic amino acids were retained in the common ancestor of the extant true bugs. These molecular apomorphies are located in 553 orthologous genes, which suggests the common ancestor of the extant true bugs may have experienced large-scale evolution at the genome level.

Silica coated upconversion nanoparticles: a versatile platform for the development of efficient theranostics.

Next generation theranostic devices will rely on the smart integration of different functional moieties into one system. These individual chemical elements will have a variety of desired chemical and physical properties and will need to behave in a multifunctional manner. Researchers have used upconversion nanoparticles (UCNPs) as a basis for superior imaging probes to locate cancerous lesions. The features of these nanoparticles, such as large anti-Stokes shifts, sharp emission bands, long-lived luminescence, and high resistance to photobleaching, have produced versatile probes. One way to improve these probes is to add a layer of dense or mesoporous silica to the outer surface of UCNPs (UCNP@SiO2). These modified UCNPs are chemically stable and much less cytotoxic than the original UCNPs. In addition, their surface can be easily modified to introduce various functional groups (e.g., -NH2, -COOH, -SH) via silanization, which facilitates conjugations with various biological molecules for multimodal imaging or synergetic therapeutics. This versatility makes UCNP@SiO2 particles excellent platforms for the construction of efficient theranostics. In this Account, we provide a comprehensive summary of recent progress in the development of UCNP@SiO2 nanocomposites for theranostics in the hope of speeding their translation into the clinic. We first discuss the major design principles and protocols for engineering various nanocomposites based on UCNP@SiO2 structures including those coated with dense silica, mesoporous silica, or hollow mesoporous silica. Next we summarize several representative efforts that probe the relaxivity mechanisms of these nanostructures as a way to optimize magnetic resonance sensitivity, multimode cancer imaging, near-infrared light-triggered chemotherapy, photodynamic therapy, and synergetic therapy (the combination of radiotherapy with chemotherapy, thermotherapy, or photodynamic therapy) using UCNP@SiO2-based theranostics. By rational integration of a wide range of features that convey multiple functions (such as imaging and therapy) into the structure or onto the surfaces of UCNP@SiO2, the constructed theranostics show promise for multimodal cancer imaging, biosensing, and effective cancer therapy. Finally, we discuss the limitations of UCNP@SiO2 nanostructures, the difficulties in the design of smart theranostics, and their potential role in clinical cancer research.

Phylogenetic divergences of the true bugs (Insecta: Hemiptera: Heteroptera), with emphasis on the aquatic lineages: the last piece of the aquatic insect jigsaw originated in the Late Permian/Early Triassic.

Heteroptera are among the most diverse hemimetabolous insects. Seven infraorders have been recognized within this suborder of Hemiptera. Apart from the well-established sister-group relationship between Cimicomorpha and Pentatomomorpha (= Terheteroptera), the two terminal lineages, the relationships among the other five infraorders are still controversial, of which three (Gerromorpha, Nepomorpha and Leptopodomorpha) are intimately connected to aquatic environments. However, the various and often conflicting available phylogeny hypotheses do not offer a clear background for a connection between diversification and palaeoenvironments. In this study, a molecular data set representing 79 taxa and 10 149 homologous sites is used to infer the phylogenetic relationships within Heteroptera. Bayesian inference, maximum-likelihood and maximum parsimony analyses were employed. The results of phylogenetic inferences largely confirm the widely accepted phylogenetic context. Estimation of the divergence time based on the phylogenetic results revealed that Gerromorpha, Nepomorpha and Leptopodomorpha originated successively during the period from the Late Permian to Early Triassic (269-246 Ma). This timescale is consistent with the origin and radiation time of various aquatic holometabolans. Our results indicate that the aquatic and semi-aquatic true bugs evolved under environmental conditions of high air temperature and humidity in an evolutionary scenario similar to that of the aquatic holometabolans.

STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer.

In breast cancer, a subset of tumor-initiating cells (TIC) or "cancer stem cells" are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current breast cancer stem cell markers (e.g., CD44(high) /CD24(low/neg) , ALDH positive) have allowed enrichment for such cells, they are not universally expressed and may actually identify distinct TIC subpopulations in the same tumor. Thus, additional markers of functional stem cells are needed. The STAT3 pathway is a critical regulator of the function of normal stem cells, and evidence is accumulating for its important role in breast cancer stem cells. However, due to the lack of a method for separating live cells based on their level of STAT3 activity, it remains unknown whether STAT3 functions in the cancer stem cells themselves, or in surrounding niche cells, or in both. To approach this question, we constructed a series of lentiviral fluorescent (enhanced green fluorescent protein, EGFP) reporters that enabled flow cytometric enrichment of cells differing in STAT3-mediated transcriptional activity, as well as in vivo/in situ localization of STAT3 responsive cells. Using in vivo claudin-low cell line xenograft models of human breast cancer, we found that STAT3 signaling reporter activity (EGFP(+) ) is associated with a subpopulation of cancer cells enriched for mammosphere-forming efficiency, as well as TIC function in limiting dilution transplantation assays compared to negative or unsorted populations. Our results support STAT3 signaling activity as another functional marker for human breast cancer stem cells thus making it an attractive therapeutic target for stem-cell-directed therapy in some breast cancer subtypes.

Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells.

Gene amplifications in the 17q chromosomal region are observed frequently in breast cancers. An integrative bioinformatics analysis of this region nominated the MAP3K3 gene as a potential therapeutic target in breast cancer. This gene encodes mitogen-activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), which has not yet been reported to be associated with cancer-causing genetic aberrations. We found that MAP3K3 was amplified in approximately 8-20% of breast cancers. Knockdown of MAP3K3 expression significantly inhibited cell proliferation and colony formation in MAP3K3-amplified breast cancer cell lines MCF-7 and MDA-MB-361 but not in MAP3K3 non-amplified breast cancer cells. Knockdown of MAP3K3 expression in MAP3K3-amplified breast cancer cells sensitized breast cancer cells to apoptotic induction by TNFα and TRAIL, as well as doxorubicin, VP-16 and fluorouracil, three commonly used chemotherapeutic drugs for treating breast cancer. In addition, ectopic expression of MAP3K3, in collaboration with Ras, induced colony formation in both primary mouse embryonic fibroblasts and immortalized human breast epithelial cells (MCF-10A). Combined, these results suggest that MAP3K3 contributes to breast carcinogenesis and may endow resistance of breast cancer cells to cytotoxic chemotherapy. Therefore, MAP3K3 may be a valuable therapeutic target in patients with MAP3K3-amplified breast cancers, and blocking MAP3K3 kinase activity with a small molecule inhibitor may sensitize MAP3K3-amplified breast cancer cells to chemotherapy.

[Changes of CD4 + CD25 + Foxp3 + regulatory T cells in the peripheral blood and their correlation with insulin resistance in different stages of prostate cancer].

OBJECTIVE: To investigate the changes of CD4 + CD25 + Foxp3 + regulatory T cells in the peripheral blood mononuclear cells (PBMC) and their association with insulin resistance in different stages of prostate cancer (PCa). METHODS: Using flow cytometry, we counted the CD4+ CD25 + Foxp3 + regulatory T cells in the PBMCs of 62 PCa patients (5 cases of TNM stage I, 16 cases of stage II, 21 cases of stage III, and 20 cases of stage IV) and 42 normal healthy controls, and calculated their proportion in the CD4+ T-lymphocytes. We determined the levels of fast blood glucose (FBG) and fast insulin (FINS) for the insulin resistance index (HOMA-IR), obtained the serum IGF-1 level by ELISA, and analyzed the relationship of the count and proportion of CD4+ CD25+ Foxp3+ regulatory T cells with insulin resistance by comparison between the PCa patients and normal healthy controls. RESULTS: Compared with the control group, the PCa patients showed significantly increased HOMA-IR (3.68 ± 1.42 vs 6.68 ± 1.66), decreased level of serum IGF-1 ([164.56 ± 30.58] vs [96.39 ± 21.21] ng/ml), and elevated count ([1.99 ± 0.78 ] x 10(7) vs [3.55 ± 0.29] x 10(7)) and proportion ([5.33 ± 0.65] vs [13.88 ± 0.96]%) of CD4 + CD25 + Foxp3 regulatory T cells in the PBMCs. The TNM stage was correlated positively with the count and percentage of CD4 + CD25+ Foxp3 + regulatory T cells and HOMA-IR, but negatively with the level of serum IGF-1. Meanwhile, the count and percentage of CD4 + CD25 + Foxp3 + regulatory T cells were found to have a positive correlation with HOMA-IR (r = 0.722 and 0.689, P < 0.01) but a negative correlation with the level of serum IGF-1 (r = -0.747 and -0.896, P < 0.01). CONCLUSION: The count and proportion of CD4+ CD25 + Foxp3 + regulatory T cells in the peripheral blood and insulin resistance increase with the elevated stage of PCa. CD4 + CD25 + Foxp3 + regulatory T cells may be involved in the occurrence and progression of PCa by regulating insulin resistance.

Differential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells.

The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is widely used in the treatment of human cancers. However, the mechanism underlying intrinsic tumor resistance to CDDP remains elusive. Here, we demonstrate that treatment with CDDP resulted in down-regulation of c-Jun expression via caspase-9-dependent cleavage of c-Jun at Asp-65 and MEKK1-mediated ubiquitylation and degradation of c-Jun in CDDP-sensitive cancer cells. In contrast, activation of JNK2 (but not JNK1) phosphorylated and up-regulated the expression of c-Jun in CDDP-resistant cells. Activated c-Jun bound to the promoter regions of the MDR1 gene and promoted the expression of MDR1. Expression of a cleavage-resistant c-Jun mutant (D65A) suppressed CDDP-induced apoptosis of CDDP-sensitive cells, whereas depletion of JNK2, c-Jun, or MDR1 in CDDP-resistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2(-/-) mice were more sensitive to CDDP compared with those in JNK2(+/+) mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment with CDDP and indicate that c-Jun is a molecular target for improving cancer therapy.