Clinicopathological characteristics of the SOX10+ subset of HER2+ breast cancer.

HER2-positive breast cancers (HER2+ BC) are a heterogeneous group of tumors with variable clinical behavior. SOX10, a biomarker that has been studied in the context of breast carcinomas, especially triple-negative breast carcinomas (TNBC), has yet to be systematically investigated in a cohort of HER2+ BC. Our aim was to investigate the clinicopathological features of the SOX10+ subset of HER2+ BC. 80 HER2+/ER- invasive breast carcinomas were stained for SOX10. All SOX10+ cases and a matched number of SOX10- cases were also stained for vimentin and androgen receptor (AR). 18 % (14/80) of our cases were SOX10+. SOX10 expression was seen in both IHC positive (3+) and equivocal (2+) but ISH-amplified cases. The SOX10+ tumors were significantly associated with both greater vimentin expression (36 % vs 0 %, p = 0.0407) and less AR expression (14 % vs 100 %, p = 0.0001) compared to SOX10- tumors. Interestingly, the vimentin+/AR- subset of our SOX10+ cases showed uniformly apocrine-like morphology, while all SOX10- cases, including those with apocrine-like morphology, were vimentin-/AR+. Our findings suggest that SOX10+/HER2+ BC are more likely to show a peculiar apocrine-like, vimentin+/AR- phenotype as compared to SOX10-/HER2+ BC.

Exosomes derived from myeloid-derived suppressor cells facilitate castration-resistant prostate cancer progression via S100A9/circMID1/miR-506-3p/MID1.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is a major cause of recurrence and mortality among prostate cancer (PCa) patients. Myeloid-derived suppressor cells (MDSCs) regulate castration resistance in PCa. Previously, it was shown that intercellular communication was efficiently mediated by exosomes (Exos), but the role and the mechanism of MDSC-derived Exos in CRPC progression was unclear. METHODS: In this study, the circRNA expression profiles in PC3 cells treated with MDSC-Exo and control cells were investigated using a circRNA microarray. RESULTS: The data showed that circMID1 (hsa_circ_0007718) expression was elevated in PC3 cells treated with MDSC-Exo. Moreover, high circMID1 expression was found in PCa compared with benign prostatic hyperplasia (BPH) tissues and in CRPC patients compared with hormone sensitive prostate cancer (HSPC) patients. Further studies showed that MDSC-Exo accelerated PCa cell proliferation, migration, and invasion, while circMID1 deficiency inhibited MDSC-Exo-regulated CRPC progression in vitro and in vivo. Mechanistically, MDSC-derived exosomal S100A9 increased circMID1 expression to sponge miR-506-3p, leading to increased MID1 expression and accelerated tumor progression. CONCLUSION: Together, our results showed that a S100A9/circMID1/miR-506-3p/MID1 axis existed in MDSC-Exo-regulated CRPC progression, which provided novel insights into MDSC-Exo regulatory mechanisms in CRPC progression.

MiR-221-3p targets HIPK2 to promote diabetic wound healing.

Diabetic foot ulcer is a severe complication of diabetes and is prone to being a chronic non-healing wound. We previously demonstrated that endothelial progenitor cell-derived exosomes, which contain miR-221-3p, alleviate diabetic ulcers. Here, to explore the mechanisms underlying this wound healing, we investigated the potential angiogenic effects of miR-221-3p in vitro using cultured human umbilical vein endothelial cells (HUVECs) and in vivo using a streptozotocin-induced mouse model of diabetes. We found that miR-221-3p promoted HUVEC viability, migration, and capillary-like tube formation. HUVECs cultured in high glucose showed up-regulated expression of homeodomain-interacting protein kinase 2 (HIPK2), a predicted target of miR-221-3p that may decrease angiogenesis. Knockdown of HIPK2 enhanced high glucose-suppressed HUVEC viability, migration, and tube formation, counteracting the effects of high glucose. Using a dual luciferase reporter assay, we found that HIPK2 was indeed a direct target of miR-221-3p. Subcutaneous injection of miR-221-3p agomir into diabetic mice promoted wound healing and suppressed HIPK2 expression in wound margin tissue. These findings indicate that HIPK2, as a direct target of miR-221-3p, contributes to the regulatory role of miR-221-3p in diabetic wound healing and may be a novel therapeutic target for diabetic foot ulcer.

Fatal adrenal crisis due to Addison's disease arising in the context of autoimmune polyglandular syndrome type 1.

The autoimmune polyglandular syndromes (APS) are rare immune-mediated endocrinopathies causing destruction of multiple endocrine and non-endocrine organs. Involvement of adrenal glands associated with any type of APS results in Addison's disease. While patients with Addison's disease often suffer from symptoms of neuroglycopenia, lethal hypotension and hypoglycemia are uncommon. Here, we report a fatal case of APS type 1 with hypotension and profound hypoglycemia in a 24-year-old man who was found unconsciousness at home and progressively evolved into pulseless electrical activity. Although his condition was initially considered to be possibly due to drug toxicity, subsequent drug screening tests failed to detect alcohol or any other substances. Emergent medical evaluation revealed severe hypotension (51/30 mm/Hg) and profound hypoglycemia (blood glucose of 20-30 mg/dl). Despite vigorous supportive care, the patient died following 3 days of respiratory dependency due to irreversible anoxic brain injury. Postmortem examination revealed severely atrophic adrenal glands with lymphocytic infiltration. Subsequent review of the patient's medical history and correlation with autopsy findings confirmed the presence of multiple organ involvement, consistent with APS type 1. This case serves as a reminder for forensic pathologists that death from an acute adrenal (Addisonian) crisis, while uncommon, should remain a differential diagnostic consideration. Furthermore, it underscores the fact that Addison's disease can occur as part of a constellation of autoimmune manifestations within the context of an underlying polyglandular syndrome, such as APS type 1.

Sustainable wastewater treatment by deep eutectic solvents and natural silk for radioactive iodine capture.

The pollution from nuclear leaks and nuclear disasters (e.g. radioactive iodine) would cause serious harm to human beings and ecosystems for many years. Cocoon silk and deep eutectic solvents (DESs) are both green substances. DESs are easily synthesized, cheap, highly biocompatible and highly biodegradable. Here, we combine the removal of organic dyes and the capture of radioactive iodine by using green DES-pretreated cocoon silk. It is the first time organic dyes have been removed from wastewater by DES-disrupted silk for the purpose of favourably removing iodine. Organic dyes-captured DES-pretreated cocoon silk could be used to capture iodine efficiently. It opens a new route to dispose of one waste from nuclear energy with organic dyes from wastewater captured by green solvents-pretreated natural silk.

The miR-134 attenuates the expression of transcription factor FOXM1 during pluripotent NT2/D1 embryonal carcinoma cell differentiation.

Transcription factor FOXM1 plays a critical role in maintenance of stem cell pluripotency through stimulating the transcription of pluripotency-related genes in mouse pluripotent stem cells. In this study, we have found that the repression of FOXM1 expression is mediated by FOXM1 3'UTR during retinoic acid-induced differentiation of human pluripotent NT2/D1 embryonal carcinoma cells. FOXM1 3'UTR contains a microRNA response element (MRE) for miR-134, which has been shown to attenuate the expression of pluripotency-related genes post-transcriptionally during mouse embryonic stem cell differentiation. We have determined that miR-134 is induced during RA-induced differentiation of NT2/D1 cells and the overexpression of miR-134 represses the expression of FOXM1 protein but not FOXM1 mRNA. Furthermore, the expression of OCT4 is diminished by FOXM1 knockdown and the OCT4 promoter is regulated directly by FOXM1, suggesting that FOXM1 is required for maintaining the expression of OCT4 in NT2/D1 cells. Together, our results suggest that FOXM1 is essential for human pluripotent stem cells and miR-134 attenuates its expression during differentiation.

Ultrashort echo time (UTE) imaging of receptor targeted magnetic iron oxide nanoparticles in mouse tumor models.

PURPOSE: The purpose of this study was to investigate an ultrashort echo time (UTE) imaging approach for improving the detection of receptor targeted magnetic nanoparticles in cancer xenograft models using positive contrast. MATERIALS AND METHODS: Iron oxide nanoparticle (IONP) conjugated with tumor targeting ligands were prepared. A 3D UTE gradient echo sequence with the shortest TE of 0.07 msec was evaluated on a 3T magnetic resonance imaging (MRI) scanner using IONP solution, cancer cells bound with targeted IONPs and orthotopic human pancreatic, and breast cancer mouse models administered tumor targeting IONPs. A simulation was performed to analyze contrast-to-noise ratios (CNR) of UTE images and subtraction of the images obtained UTE and longer TE (SubUTE). T2-weighted imaging and T2 relaxometry mapping were applied for comparison and validation. RESULTS: UTE and SubUTE images showed positive contrast in pancreatic tumors accumulated with EGFR targeted ScFvEGFR-IONPs and mammary tumors accumulated with uPAR targeted ATF-IONPs. The positive contrast observed in UTE images was consistent with the negative contrast observed in the T2-weighted images. A flip angle of 10° and a maximal possible TE for the second echo are suitable for SubUTE imaging. CONCLUSION: UTE imaging is capable of detecting tumor targeted IONPs in vivo with positive contrast in molecular MRI applications.

Dual fragmentation modes of the explosively dispersed granular materials.

Granular materials subjected to blast loading caused by a central explosion exhibit a distinctive dual jetting phenomenon. A large number of fine particle jets are ejected from the outer edge of the charge upon the reflection of the shock wave from the free surface, and are soon overtaken and overlapped by a second set of much thicker particle jets from the inner edge. Our numerical studies suggest that these two distinct sets of particle jets arise from a subsequent fragmentation of the outer and inner particle layers formed during shock interaction. The instability onset of the inner particle layer, which remains intact after the spallation of the outer particle layer, corresponds to the destabilizing viscous forces prevailing over the stabilizing inertial forces. The physical mechanism responsible for the spallation of the outer particle layer is accounted for by a three-phase cavitation model consisting of nucleation, unconditioned and conditioned growth of voids. The theoretically predicted fragmentation onset and fragment size are well consistent with the experimental results. Moreover, by incorporating the moisture effect into the granular material model, results of the cavitation model indicate an increased number of jets generated by saturated particles, as observed in experiments. With minor shock energy being consumed on the saturated particle compaction thanks to the remarkably low compressibility of saturated particles, the shock wave retains the steep front during propagation and subsequently produces a sharp reflection wave leading to a considerably higher strain relaxation rate in saturated particles than that in dry particles. The pressure relaxation duration prescribes the time the activated nucleation sites are allowed to communicate with each other. Consequently nucleation sites in saturated particles have more chances to survive and fully develop than those in dry particles giving rise to smaller fragments.

[Isolation, amplification and identification of human natural CD4⁺CD25⁺ regulatory T cells in vitro].

OBJECTIVE: To establish a method for in vitro expansion of human natural CD4⁺CD25⁺ T regulatory cell (Treg) cells for clinical study and immunotherapy. METHODS: Human natural CD4⁺CD25⁺ Treg were isolated from peripheral blood monocyte cells (PBMCs) by magnetic activated cell sorting (MACS) and expanded by CD3/CD28 expansion beads, IL-2 and rapamycin. The number and the viability of the freshly isolated and expanded Treg were detemined by trypan blue staining. The phenotype and the purity of the freshly isolated and expanded Treg were analyzed by FACS. Treg suppression activity was assessed by mixed lymphocyte reaction (MLR) assay. RESULTS: Human natural Treg were expanded up to 2 000 folds after 3 weeks in culture, and the activity was more than 97%. The expanded Treg retained Treg phenotype as shown by their freshly isolated counterparts, and the purity of CD4⁺CD25⁺FoxP3⁺ Treg was (94.22 ± 2.12)%. The expanded Treg demonstrated a similar potent suppression of both proliferating auto- and allo- CD4⁺CD25⁻ effector T cells in vitro in a cell number-dependent manner. CONCLUSION: An in vitro expansion of human natural Treg was established to obtain large numbers of human Treg with highly suppressive phenotype and function, thereby providing a solution to the availability of sufficient human natural Treg in clinical study and immunotherapy.

Meta-analysis of postoperative urinary incontinence incidence and risk factors in HoLEP.

Objective: To systematically identify and quantify the incidence and risk factors of postoperative urinary incontinence (UI) in holmium laser enucleation of the prostate (HoLEP), aiming to provide a basis for intervention strategies. Methods: Relevant studies on postoperative UI in HoLEP were searched in databases including PubMed, Web of Science, EMBase, CNKI, Wanfang Data Knowledge Service Platform, VIP and CBMdisc, with the search period up to April 2024. Titles, abstracts and full texts were screened using the Endnote application. Studies meeting the inclusion and exclusion criteria underwent quality assessment and data extraction. The incidence of postoperative UI and/or adjusted or unadjusted odds ratios (OR), relative risks or ratios were recorded, and analysis was conducted using Stata 15.0 software. Results: A total of 17 studies encompassing 7939 patients were included. The pooled incidence of UI after HoLEP was 1.12, 95% CI (1.11-1.13); the 3-month postoperative incidence was 1.06, 95% CI (1.05-1.06); the 6-month postoperative incidence was 1.04, 95% CI (1.03-1.05); the 12-month postoperative incidence was 1.05, 95% CI (1.03-1.06); and the incidence of permanent UI after HoLEP was 1.01, 95% CI (1.00-1.01). The occurrence of UI after HoLEP exhibited a time-dependent variation. The risk factors for UI after HoLEP included the following: age (OR = 1.03, 95% CI: 1.01-1.06); body mass index (BMI; OR = 1.10, 95% CI: 1.01-1.20); prostate volume (OR = 1.77, 95% CI: 1.39-2.27); prostate-specific antigen (PSA) (OR = 0.98, 95% CI: 0.87-0.92); International Prostate Symptom Score (IPSS) (OR = 0.94, 95% CI: 0.83-1.07). Conclusion: The results of this study indicate a decreasing trend in the incidence of postoperative UI after HoLEP over time, with a time-dependent change. Age, BMI, prostate volume, PSA and IPSS are risk factors for postoperative UI after HoLEP. Age and prostate volume have a significant impact on UI. Therefore, preoperative assessment and intervention for these factors are crucial in reducing the occurrence of postoperative UI in HoLEP.

Postoperative urinary incontinence incidence and risk factors in HoLEP The results of this study indicate a decreasing trend in the incidence of postoperative urinary incontinence after HoLEP over time, with a time-dependent change. Age, body mass index, prostate volume, diabetes and preoperative urinary retention are risk factors for postoperative urinary incontinence after HoLEP. Age and prostate volume have a significant impact on urinary incontinence. Therefore, preoperative assessment and intervention for these factors are crucial in reducing the occurrence of postoperative urinary incontinence in HoLEP.

Machine learning-based cell death marker for predicting prognosis and identifying tumor immune microenvironment in prostate cancer.

Background: Prostate cancer (PCa) incidence and mortality rates are rising, necessitating precise prognostic tools to guide personalized treatment. Dysregulation of programmed cell death pathways in tumor suppression and cancer development has garnered increasing attention, providing a new research direction for identifying biomarkers and potential therapeutic targets. Methods: Integrating multiple database resources, we constructed and optimized a prognostic signature based on the expression of programmed cell death-related genes (PCDRG) using ten machine learning algorithms. Model performance and prognostic effects were further evaluated. We analyzed the relationships between signature and clinicopathological features, somatic mutations, drug sensitivity, and the tumor immune microenvironment, and constructed a nomogram. The expression level of PCDRGs were evaluated and compared. Results: Of 1560 PCDRGs, 149 were differentially expressed in PCa, with 34 associated with biochemical recurrence. The PCDRG-derived index (PCDI), constructed using the random forest algorithm, exhibited optimal prognostic performance, successfully stratifying PCa patients into two groups with significant prognostic differences. Patients with high PCDI scores exhibited poorer survival and lower immunotherapy benefit. PCDI was closely associated with the infiltration of specific immune cells, particularly positive correlations with macrophages and T helper cells, and negative correlations with neutrophils, suggesting that PCDI may influence the tumor immune microenvironment, thereby affecting patient prognosis and treatment response. PCDI was associated with age, pathological stage, somatic mutations, and drug sensitivity. The PCDI-based nomogram demonstrated excellent performance in predicting biochemical recurrence in PCa patients. Finally, the differential expression of these PCDRGs was verified based on cell lines and PCa patient expression profile data. Conclusion: This study developed an effective prognostic indicator for prostate cancer, PCDI, using machine learning approaches. PCDI reflects the link between aberrant programmed cell death pathways and disease progression and treatment response.

Retrospective Evaluation of the Efficacy of Electrophysiological Appropriate Techniques for Nocturia Following Radical Prostatectomy.

This study retrospectively examines the effectiveness of low-frequency electrical stimulation for addressing nocturia in patients experiencing urinary incontinence after undergoing radical prostatectomy. We reviewed the outcomes of 32 patients who had undergone radical prostatectomy and subsequently experienced urinary incontinence. These patients were divided into the control group (n = 16) who received pelvic floor muscle training and the treatment group (n = 16) who underwent electrophysiological appropriate technique treatment in conjunction with pelvic floor muscle training. We assessed changes in nocturnal voided volume, polyuria index, and nocturia-related quality of life at three different time points: before treatment, after 2 weeks, and at the 3-month follow-up. After 3-month follow-up, both groups exhibit reductions in nocturnal voided volume, and polyuria index compared with baseline and the 2-week mark (p < .05). Treatment group outperformed the control group (p < .05). The quality of life in the treatment group remained consistently high, while the control group did not show a statistically significant difference from baseline (p > .05). The total effective rate was significantly higher in the treatment group (93.75%) than in the control group (75.00%, p = .044). This retrospective analysis suggests that electrophysiological appropriate technique treatment effectively mitigates nocturnal, leading to improved quality of life in patients with urinary incontinence following radical prostatectomy in the near term.

Enhanced Asymmetric Circularly Polarized Luminescence in Self-Organized Helical Superstructures Enabled by Macro-Chiral Liquid Crystal Quantum Dots.

Circularly polarized luminescent (CPL) materials have garnered considerable interest for a variety of advanced optical applications including 3D imaging, data encryption, and asymmetric catalysis. However, the development of high-performance CPL has been hindered by the absence of simple synthetic methods for chiral luminescent emitters that exhibit both high quantum yields and dissymmetry factors. In this study, we present an innovative approach for the synthesis of macro-chiral liquid crystal quantum dots (Ch-QDs/LC) and their CPL performance enhancement through doping with 4-cyano-4'-pentylbiphenyl (5CB), thus yielding a CPL-emitting generator (CEG). The Ch-QDs/LCs were synthesized, and their surfaces functionalized with a chiral mesogenic ligand, specifically cholesteryl benzoate, anchored via a lipoic acid linker. Under the regulation of chiral 2S-Zn2+ coordination complexes, the chiral LC encapsulation process promotes coordinated ligand substitution, resulting in an exceptional quantum yield of 56.3%. This is accompanied by high absorption dissymmetry factor (gabs) and luminescence dissymmetry factor (glum) values ranging from 10-3 to 10-2, surpassing most reported dissymmetry factors by at least an order of magnitude. The modular Ch-QDs/LCs demonstrate the ability to transfer chirality to the surrounding medium efficiently and manifest macro-chiral characteristics within a nematic LC matrix. Utilizing Ch-QDs/LC as an effective CPL emitter within achiral 5CB matrices enabled the system to achieve a maximum glum value of 0.35. The resultant CEG device acted as a direct CPL source, initiating enantioselective photopolymerization.

A SOX10+/AR- immunoprofile may identify a subset of low positive ER carcinomas with a wider range of ER expression.

BACKGROUND: Invasive breast carcinomas (IBC) that strongly express SOX10 are almost always negative for androgen receptor (AR). Furthermore, this SOX10+/AR- subset of IBC is nearly always estrogen receptor and progesterone receptor negative (ER-/PR-), being most commonly seen in triple negative breast carcinomas (TNBC), but also in a small subset of HER2+/ER-/PR- IBC. Following our previous work demonstrating the expression of SOX10 in a subset of IBC with "low positive" ER expression (i.e. 1-10 % ER+ staining based on CAP guidelines, here referred to as "ER-low"), we sought to investigate the expression of both SOX10 and AR in a larger cohort of ER-low tumors. As our previous work also revealed occasional SOX10 expression in IBC with >10 % ER+ staining, we also included tumors with any percentage of ER staining, as long as the staining intensity was weak (this subset is referred to as "ER-weak"). METHODS: We screened cases of HER2-/ER+ IBC diagnosed at our institution over a 10 year period, identified both ER-low and ER-weak tumors and stained both groups with SOX10 and AR. RESULTS: Strong SOX10 expression was seen in 12/25 (48 %) ER-low tumors and 13/24 (54 %) ER-weak tumors. ER staining in the SOX10+ subset of ER-weak tumors ranged from 15 %-80 % (median 25 %). As expected, AR was negative in all but 1 of the SOX10+ tumors in both groups. While case numbers in these groups were too small for a meaningful statistical analysis, we did note that all SOX10+/AR- tumors within both the ER-low and ER-weak groups were histologic grade 3. CONCLUSION: The presence of a SOX10+/AR- profile in a significant subset of ER-low tumors confirms the findings of our previous work and provides further support for the proposed functionally ER negative status of this group. Furthermore, the fact that the same SOX10+/AR- profile is seen in a roughly equal subset of ER-weak tumors suggests that a wider range of ER staining may be acceptable as "low positive" in SOX10+/AR- tumors, as long as the ER staining is of weak intensity. However, given the small number of cases in this single institution study, we emphasize the need for larger studies to establish the biological and clinical significance of this tumor subset.

Homologous recombination deficiency serves as a prognostic biomarker in clear cell renal cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a frequent malignant tumor characterized by a high degree of heterogeneity and genetic instability. DNA double-strand breaks generated by homologous recombination deficit (HRD) are a well-known contributor to genomic instability, which can encourage tumor development. It is not known, however, whether the molecular characteristics linked with HRD have a predictive role in KIRC. The discovery cohort comprised 501 KIRC patients from The Cancer Genome Atlas database. Genome and transcriptome data of HRD patients were used for comprehensive analysis. Single cell RNA sequencing (scRNA-seq) was used to verify the test results of bulk RNA-seq. In the present study, patients with a high HRD score had a worse prognosis compared with those with a low HRD score. The DNA damage response signaling pathways and immune-related signaling pathways were notably enriched in the HRD-positive subgroup. Further comprehensive analysis of the tumor microenvironment (TME) revealed that the signal of exhausted CD8+ T cells was enriched in the HRD-positive subgroup. Finally, scRNA-seq analyses confirmed that the immune-related signaling pathways were upregulated in HRD-positive patients. In conclusion, the present study not only demonstrated that a high HRD score is a valid prognostic biomarker in KIRC patients, but also revealed the TME in HRD-positive tumors.

Exploring the role of microbial proteins in controlling environmental pollutants based on molecular simulation.

Molecular simulation has been widely used to study microbial proteins' structural composition and dynamic properties, such as volatility, flexibility, and stability at the microscopic scale. Herein, this review describes the key elements of molecular docking and molecular dynamics (MD) simulations in molecular simulation; reviews the techniques combined with molecular simulation, such as crystallography, spectroscopy, molecular biology, and machine learning, to validate simulation results and bridge information gaps in the structure, microenvironmental changes, expression mechanisms, and intensity quantification; illustrates the application of molecular simulation, in characterizing the molecular mechanisms of interaction of microbial proteins with four different types of contaminants, namely heavy metals (HMs), pesticides, dyes and emerging contaminants (ECs). Finally, the review outlines the important role of molecular simulations in the study of microbial proteins for controlling environmental contamination and provides ideas for the application of molecular simulation in screening microbial proteins and incorporating targeted mutagenesis to obtain more effective contaminant control proteins.

Enhancing Pullulan Soft Capsules with a Mixture of Glycerol and Sorbitol Plasticizers: A Multi-Dimensional Study.

The plasticizer is crucial in the plant-based soft capsule. However, meeting the quality requirements of these capsules with a single plasticizer is challenging. To address this issue, this study first investigated the impact of a plasticizer mixture containing sorbitol and glycerol in varying mass ratios and the performance of the pullulan soft film and capsule. The multiscale analysis demonstrates that the plasticizer mixture exhibits superior effectiveness in enhancing the performance of the pullulan film/capsule compared to a single plasticizer. Furthermore, thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy indicate that the plasticizer mixture enhances the compatibility and thermal stability of the pullulan films without altering their chemical composition. Among the different mass ratios examined, a 15:15 ratio of sorbitol to glycerol (S/G) is identified as the most optimal, leading to superior physicochemical properties and meeting the requirements for brittleness and disintegration time set by the Chinese Pharmacopoeia. This study provides significant insights into the effect of the plasticizer mixture on the performance of pullulan soft capsules and offers a promising application formula for future use.

Betapapillomaviruses in p16-Negative Vulvar Intraepithelial Lesions Associated with Squamous Cell Carcinoma.

Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (ß-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of ß-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. ß-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of ß-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva.

Stable expression of FoxA1 promotes pluripotent P19 embryonal carcinoma cells to be neural stem-like cells.

FoxA1 belongs to the fork head/winged-helix transcription factor family and participates in stimulating neuronal differentiation of pluripotent stem cells at early stages. To explore the biological roles of FoxA1 during this process, the stable expression of a GFP-FoxA1 fusion protein was established in P19 pluripotent embryonal carcinoma cells. Although they still express pluripotency-related transcription factors such as Oct4, Nanog, and Sox2, the generated P19 GFPFoxA1 cells exhibited a decreased activity of alkaline phosphatase and an increased expression of SSEA-3 compared with P19 cells. Elevated levels of nestin expression and prominin-1+ populations were observed in P19 GFPFoxA1 cells, implicating that the stable expression of FoxA1 promoted P19 cells to gain partial characteristics of neural stem cells. Furthermore, the promoter of nestin was confirmed to be bound and activated by FoxA1 directly. The expression of neuron-specific marker tubulin betaIII also existed in P19 GFPFoxA1 cells. P19 GFPFoxA1 cells showed an earlier onset of differentiation during RA-induced neuronal differentiation, evidenced by a more rapid change on the Nanog decrease and the tubulin betaIII increase. Thus, overexpression of FoxA1 alone may promote pluripotent P19 cells to become neural stem-like cells.

HER2-positive/ER-low breast carcinoma shows a response to neoadjuvant chemotherapy similar to that of HER2-positive/ER-negative breast carcinoma.

Negative expression of estrogen receptor (ER) predicts response to chemotherapy in breast cancers (BCs). ER negative cancers are those with less than 1 % of nuclear staining. Tumors with 1-10 % staining are sub-classified as "low-positive" (ER-low). HER2 negative tumors with ER low staining are considered biologically and clinically equivalent to ER negative tumors. This study investigates whether ER low expression in HER2-positive (HER2+) BCs has different clinical behavior than ER negative HER2-positive tumors. We used a sample of 171 patients with HER2+ BCs to compare risk of residual cancer after neoadjuvant chemotherapy by different ER expression strength. Patients were classified into 3 groups: ER-negative (ER <1 %); ER-low (ER <10 %, any intensity or <33 % staining, weak intensity); and ER-high (ER = 10-33 %, moderate to strong intensity or >33 %, any intensity). The risk of residual cancer in patients with ER-low tumors was similar to the risk in patients with ER-negative tumors (RR = 0.76, 95 % CI: 0.30-1.93). Conversely, patients with ER-high tumors had twice the risk of residual cancer than patients with ER-negative tumors (RR = 2.20, 95 % CI: 1.46-3.31). These findings persisted after adjusting for tumor grade, clinical tumor and lymph node stage, chemotherapy regimen, and progesterone receptor status. In this cohort of patients with HER2+ BCs, ER-low tumors had a similar pathologic response to chemotherapy as ER-negative tumors suggesting similar clinical behavior. Future research should address biological explanations to these similarities between ER negative and ER low breast cancers such as HER2 enriched phenomenon.