[Clinicopathological features of breast cancer with HER2 low expression: a real-world retrospective study].

Objective: To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. Methods: The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. Results: The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (P<0.001), Ki-67 index below 35% (P<0.001), well or moderate differentiation (P<0.001) and over the age of 50 (P=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. Conclusions: The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.

[Transitional urology-current status and prospects of pediatric over-age practice].

With the continuous advancement of medicine, more children with congenital or pediatric-onset chronic urologic conditions are surviving well into adulthood, which imposes an ever-rising need for adequate transition of these patients from pediatric to adult care. Transitional Urology focuses on the health care needs of adolescents and young adults with congenital urological disorders as they transfer from pediatric to adult care, maximizing the best interests of the children. Since Shanghai Children's Medical Center has been approved for over-age continuous medical care, this paper aims to analyze the currently perceived barriers in care transition within the urological context, explore the ways of previously implemented transition models, and propose the suggestions for improvement.

[Quantitative HER2 mRNA assay in breast cancer with HER2 immunohistochemistry 0].

Objective: To investigate HER2 mRNA expression in breast cancer with HER2 immunohistochemistry (IHC) 0 and to analyze the feasibility of distinguishing between the tumor with HER2 µltra-low expression and the one without expression of HER2 (no staining by IHC) by HER2 mRNA level preliminarily. Methods: HER2 mRNA was analyzed by reverse transcription digital PCR in 41 cases of formalin-fixed paraffin-embedded surgical tissue samples of invasive breast cancer obtained between January 2020 and March 2023 at Peking Union Medical College Hospital. The cohort included 21 HER2 IHC 1+ and 20 IHC 0 (12 ultra-low and 8 non-expression of HER2). HER2 mRNA expression level was quantitatively evaluated by the FAM (HER2)/VIC (reference gene) ratio. Results: The expression of HER2 mRNA for the cases with 1+, ultra-low, and non-expression of HER2 by IHC was 0.30 to 1.78 (average 0.90, median 0.82), 0.55 to 1.51 (average 0.93, median 0.90) and 0.22 to 0.78 (average 0.41, median 0.36), respectively. For the mean and median HER2 mRNA levels, there was no significant difference between HER2 IHC 1+ and HER2 ultra-low expression diseases (P=0.757). A remarkable difference in HER2 gene expression was found between the tumors with 1+ and non-expression of HER2 by IHC (P=0.002). And, HER2 ultra-low cases contained statistically higher levels of HER2 mRNA compared with non-expression of HER2 subgroup by IHC (P=0.001). Conclusions: Based on HER2 mRNA, HER2 non-expression and HER2 weak expression (including HER2 IHC 1+ and ultra-low) belong to two different types of the tumor and the disease with HER2 IHC 1+ and HER2 ultra-low expression may be the same. It is necessary to further test the performance of HER2 mRNA detection for stratifying the HER2 weak expression subgroup and to determine the threshold.

[PIK3CA gene mutations in Chinese women with HR+/HER2- breast cancer].

Objective: To investigate the spectrum of PIK3CA gene mutations in Chinese women with hormone receptor positive and HER2 negative (HR+/HER2-) breast cancer, to provide the genetic evidence for identifying potential beneficiaries from specific PI3K isoform inhibitors in Chinese women with breast cancer and to develop detection strategies. Methods: A total of 365 breast cancer specimens archived at the Peking Union Medical College Hospital, Beijing, China from January 2017 to October 2017 were screened. Among these patients, 186 HR+/HER2- women with invasive breast cancer were collected. PIK3CA gene mutations were detected using next generation sequencing technology. The gene variant features were then analyzed and compared with reported data. Results: Among the 186 HR+/HER2- breast cancer cases, 40 (21.5%,40/186) cases harbored PIK3CA gene mutations. Exons 9 and 20 of PIK3CA mutations occurred in 92.5%(37/40)of the tumors, which included E545K, E545G, Q546K, E542K, Q546R, P539R, E547D, H1047R, H1047L, H1047Q and N1044Y. Only one case harbored the exon 7 C420R mutation. Additionally, exons 1 (F83C) and 5 (G364R) uncommon mutations were discovered respectively in 2 cases. Based on the finding, 85.0% (34/40) of cases with known mutations could be detected using companion diagnostic methods. Moreover, 25.0% (10/40) of patients had two or three variants, which were composed of E726K/N345K, H1047Q/N345K, H1047R/G364R, H1047R/E453K, E545G/E726K, E542K/E726K, E542K/H1047R, E545K/H1047R/H1047L and E545K/E547D. The lymph node positive rate in these patients with PIK3CA mutation was remarkably higher than those without (i.e., wild type, P<0.05). Conclusions: In this group of HR+/HER2- breast cancer patients, common PIK3CA gene mutations account for the vast majority of the mutations. New rare variants in PIK3CA are also identified while their clinical significance needs to be further studied in a large cohort and/or multi-center study.

[Application of diffusion-weighted magnetic resonance imaging in evaluating the efficacy of radiotherapy and chemotherapy for esophageal cancer].

This study was a prospective single arm trial conducted in Zhejiang Jinhua Guangfu hospital from February 2018 to June 2020. A total of 39 patients (32 males and 7 females) with esophageal cancer, aged from 44 to 82 (69±9) years were enrolled. Diffusion weighted magnetic resonance imaging(MR-DWI) was implemented to evaluate the changes of apparent diffusion coefficient(ADC) value before and after chemoradiotherapy. The results showed that the ADC value after chemoradiotherapy was higher than that before treatment[(2.03±0.42)×10⁻³ mm 2/s vs (1.60±0.28)×10⁻³ mm2/s], and there was a positive correlation between the increase of ADC value and the prognosis of patients.

Wharton's Jelly-derived mesenchymal stem cells suppress apoptosis of nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway.

OBJECTIVE: Aberrant apoptosis of nucleus pulposus cells (NPCs) is one of the most remarkable pathological changes in intervertebral disc degeneration (IDD) development. Albeit the advances in the application of stem cell-based therapy in IDD treatment, the molecular mechanisms underlying the anti-apoptotic actions of mesenchymal stem cell (MSC) remain poorly elucidated. PATIENTS AND METHODS: The expression patterns of apoptosis-related proteins and Wnt/ß-catenin-related genes in NP samples isolated from patients with mild or severe IDD were compared by performing immunoblot assay and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. NPCs were in vitro treated with compression to induce apoptosis and then co-cultured with Wharton's Jelly-derived MSCs without direct interaction. After that, flow cytometry was carried out to detect the apoptosis rate of NPCs and the activity of Wnt/ß-catenin pathway was determined. DKK-1 was used to inhibit Wnt signaling, in prior to evaluation of the effects of WJ-MSCs on apoptosis within the co-cultured NPCs. RESULTS: Compared to the mild IDD group, there was a significant increase in the expression of Caspase-3 and Bax in the NP tissues from severe IDD patients, whereas Bcl-2 displayed an opposite result. In addition, the expression of Wnt 3a, Wnt 5a, Wnt 10a, GSK-3ß, cyclinD1 and ß-catenin was notably augmented in parallel with IDD progression. After compression treatment, the proportion of apoptotic NPCs was increased, which was then dramatically reversed by WJ-MSCs co-culture. Likewise, WJ-MSCs suppressed compression-induced Wnt-related gene expression and blocking Wnt/ß-catenin pathway using DKK-1 enhanced the anti-apoptotic impacts of WJ-MSCs. In the presence of DKK-1, there was no significant difference between NPCs co-cultured with WJ-MSCs and those cells cultured alone. CONCLUSIONS: WJ-MSCs attenuate the compression-induced apoptosis in NPCs and inhibit the activation of Wnt/ß-catenin signaling. Blocking Wnt/ß-catenin pathway further facilitates the actions of WJ-MSCs in anti-apoptosis, indicating that Wnt/ß-catenin signaling plays a crucial role in this process and may function as a potential therapeutic target for IDD treatment.

[Advances in the research of virtual reality technology for pain intervention after burns].

Pain is one of the most common complications of burn patients. Burn from onset to rehabilitation is a long and complex process, during which dressing change, debridement, operation, and rehabilitation may cause different degrees of pain to the patients. As one of the means of non-pharmaceutical pain management, the interventional effect of virtual reality technology has gradually been recognized by more and more researchers. This paper reviewed the definition, the interventional mechanisms, and the interventional effect on burn pain of virtual reality technology, to provide a reference for clinical application of virtual reality technology in pain management of burn patients.

Research Progress on the Molecular Mechanisms of Toxicology of Ethanol-Aconitine Induced Arrhythmia.

ABSTRACT: Aconitum is one of the most widely used Chinese herbal medicines, and aconitine is the major toxic component in it. Aconitine can induce a variety of arrhythmias, resulting in death. Acute ethanol consumption causes arrhythmia as well. Poisoning cases caused by aconitum medicinal liquor are frequently encountered in the practice of forensic medicine. The molecular mechanisms of myocardial toxicity of these two drugs have much in common, and both of them affect the sodium channel, calcium channel and potassium channel of myocardial cell membrane and so on. This paper analyzes and discusses the possible co-effects of ethanol-aconitine on cardiomyocyte channel proteins, by reviewing researches on the mechanism of cardiotoxicity of ethanol and aconitine in recent years, in order to provide ideas and references for the research on the molecular mechanism of arrhythmia caused by combined poisoning.

[Advances in the research of pain assessment and non-drug intervention in burn children].

Children are a high-risk group of burn, and burn pain is a special type of pain. Because children of different ages have different cognitive ability and behavioral response to pain, thus it is particularly difficult to effectively evaluate the pain. It is very important for medical staff to understand the pain of children, to define the adverse reactions of pain, to evaluate and take appropriate pain intervention measures in time and effectively. In this paper, different evaluation methods of burn pain in children and non-drug intervention related measures were reviewed in order to provide references for clinical practice.

[HER2 gene status and mRNA expression in immunohistochemistry 1+ breast cancer].

Objective: To investigate human epidermal growth factor 2 (HER2) gene status and in situ mRNA expression in breast cancers with immunohistochemistry(IHC) 1+ , and to reveal HER2 positive rate in these patients to provide reference data for obtaining precise HER2 results and modifying relevant clinical strategy to breast cancer. Methods: Sixty-five IHC 1+ formalin-fixed and paraffin-embedded samples of invasive breast carcinoma of no special type (IBC-NST) were collected by surgical operation at Peking Union Medical College Hospital during 2011 to 2013. HER2 status and in situ mRNA expression were tested by fluorescence in situ hybridization (FISH) and RNAscope, respectively, by using tissue microarray. Metastatic lymph node was re-tested by FISH if HER2 status was equivocal or negative and with high expression of mRNA in the primary lesion. Results: Four of 65 samples (6.2%) were FISH positive, which included 2 cases of HER2/CEP17>2 and average HER2 copy number>4 and 2 cases of HER2/CEP17<2 and average HER2 copy number>6. In the 4 samples of HER2 positive, 2 patients showed high in situ mRNA expression (3 scores by RNAscope), 2 patients showed moderate in situ mRNA expression (2 scores by RNAscope). In addition, 3 specimens with HER2/CEP17>2 and average HER2 copy number<4 were found in all patients, which included 2 cases of high in situ mRNA expression (3 and 4 scores by RNAscope) and 1 cases of moderate in situ mRNA expression (2 scores by RNAscope). There was no significant association between HER2 status or mRNA expression and clinicopathological characteristics, including tumor size, histopathological differentiation, lymph node metastasis and lymphovascular invasion (P>0.05). Conclusions: A small number of HER2 IHC 1+ patients exist mRNA expression by using FISH method, which suggested that these patients might benefit from anti-HER2 therapy potentially. Since the importance for patients with breast cancers to develop diagnostic and therapeutic strategies from accurate molecular typing, further studies based on a larger cohort are needed to validate our findings.

[Application of Mixed-effect Model in PMI Estimation by Vitreous Humor].

OBJECTIVES: To test the changes of the potassium （K⁺） and magnesium （Mg²âºï¼‰ concentrations in vitreous humor of rabbits along with postmortem interval （PMI） under different temperatures, and explore the feasibility of PMI estimation using mixed-effect model. METHODS: After sacrifice, rabbit carcasses were preserved at 5 ℃, 15 ℃, 25 ℃ and 35 ℃, and 80-100 µL of vitreous humor was collected by the double-eye alternating micro-sampling method at every 12 h. The concentrations of K⁺ and Mg²âº in vitreous humor were measured by a biochemical-immune analyser. The mixed-effect model was used to perform analysis and fitting, and established the equations for PMI estimation. The data detected from the samples that were stoned at 10 ℃, 20 ℃ and 30 ℃ with 20, 40 and 65 h were used to validate the equations of PMI estimation. RESULTS: The concentrations of K⁺ and Mg²âº [f（x,y）] in vitreous humor of rabbits under different temperature increased along with PMI （x）. The relative equations of K⁺ and Mg²âº concentration with PMI and temperature under 5 ℃~35 ℃ were fK⁺（x,y）=3.413 0+0.309 2 x+0.337 6 y+0.010 83 xy-0.002 47 x² （P<0.000 1）, and fMg²âºï¼ˆx,y）=0.745 6+0.006 432 x+0.033 8 y （P<0.000 1）, respectively. It was proved that the time of deviation for PMI estimation by K⁺ and Mg²âº was in 10 h when PMI was between 0 to 40 h, and the time of deviation was in 21 h when PMI was between 40 to 65 h. CONCLUSIONS: the ambient temperature range of 5 ℃-35 ℃, the mixed-effect model based on temperature and vitreous humor substance concentrations can provide a new method for the practical application of vitreous humor chemicals for PMI estimation.

Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment.

Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.

[An adolescent with Hashimoto's encephalopathy after surgery and ¹³¹I radiotherapy for papillary thyroid carcinoma: one case report].

Hashimoto's encephalopathy is a rare brain disease. Its etiology is still unknown. In this paper, we reported a 15-year-old female patient underwent total thyroidectomy and lymph node dissection, due to a multifocal papilliferous carcinoma of the right lobus. Forty-two days after surgery, the patient was treated by ¹³¹I radiotherapy in another hospital and begun to have a headache after 48 hours. At last, the patient was diagnosed by HE on the basis of all considerations. She recovered from by i.v. Immunoglobulin. Till now, the patient has not relapsed for more than 4 years follow-up.

[Comparison of HER2 gene status between primary breast cancer and synchronous axillary lymph node metastasis].

OBJECTIVE: To investigate the discordant rate of HER2 gene status between primary breast cancer and synchronous axillary lymph node metastasis. METHODS: One hundred and fifty cases of primary breast cancer with corresponding synchronous lymph node metastases were collected, including 50 cases of HER2 FISH positive, 50 cases of HER2 FISH negative and 50 cases of HER2 FISH equivocal primary tumors, at Peking Union Medical College Hospital between May 2012 and June 2015. The HER2 gene status in lymph node metastatic tumors was analyzed by FISH, and the discordance of HER2 gene status was identified between primary and metastatic tumors. RESULTS: The incidence of discordant HER2 gene status between primary breast cancer and synchronous lymph node metastasis was 20.67%(31/150). Forty-four FISH positive, 3 FISH equivocal and 3 FISH negative cases were found in the first group of 50 patients with HER2 positive results in primary tumor. Forty seven FISH negative, 3 FISH equivocal cases were discovered in the second group of 50 patients with HER2 negative results in primary tumor. Four FISH positive, 18 FISH negative and 28 equivocal cases were observed in the third group of 50 patients with HER2 equivocal results in primary tumor. The discordance of HER2 gene status between primary tumor and lymph node metastasis in the third group of patients was significantly higher than the other two groups (P<0.05). CONCLUSIONS: Significant discordance of HER2 gene status between the primary and lymph node metastatic tumors exists. Patients with lymph node metastasis, simultaneous testing of HER2 status may be performed in both primary breast tumor and its lymph node metastasis. HER2 status of nodal metastatic lesion may be more relevant for guiding anti-HER2 target therapy.

Transformation of microcystins to 2-methyl-3-methoxy-4-phenylbutyric acid by room temperature ozone oxidation for rapid quantification of total microcystins.

Microcystins (MCs) are cyanobacterial hepatotoxins capable of accumulation into animal tissues. To determine the total microcystins in water, a novel analytical method, including ozonolysis, methylation of 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB) with methylchloroformate (MCF) and gas chromatography mass spectrometry (GC-MS) detection was developed. The results show that MCs can be oxidized by ozone to produce MMPB at ambient temperature, proving ozonation is an effective, rapid and green method for the transformation of MCs to MMPB without secondary pollution. The oxidation conditions as well as the esterification process were optimized and, subsequently applied to analysis of environmental samples. The method shows wide linear range and high sensitivity with a detection limit of 0.34 µg L(-1). The established method was successfully applied to the analysis of microcystins in water samples.

Raman scattering investigation of the quasi-one-dimensional superconductor Ta4Pd3Te16.

We have performed polarized Raman scattering measurements on the newly discovered superconductor Ta4Pd3Te16 (T(c) = 4.6 K). We observe 28 out of 33 Raman active modes, with frequencies in good accordance with first-principles calculations. Although most of the phonons observed vary only slightly with temperature and do not exhibit any asymmetric profile that would suggest strong electron-phonon coupling, the linewidth of the A(g) phonon mode at 89.9 cm(-1) shows an unconventional increase with temperature decreasing, which is possibly due to a charge-density-wave transition or the emergence of charge-density-wave fluctuations below a temperature estimated to fall in the 140-200 K range.

Superfamily of genes encoding G protein-coupled receptors in the diamondback moth Plutella xylostella (Lepidoptera: Plutellidae).

G protein-coupled receptors (GPCRs) are the largest and most versatile superfamily of cell membrane proteins, which mediate various physiological processes including reproduction, development and behaviour. The diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae), is one of the most notorious insect pests, preferentially feeding on cruciferous plants. P. xylostella is not only one of the world's most widespread lepidopteran insects, but has also developed resistance to nearly all classes of insecticides. Although the mechanisms of insecticide resistance have been studied extensively in many insect species, few investigations have been carried out on GPCRs in P. xylostella. In the present study, we identified 95 putative GPCRs in the P. xylostella genome. The identified GPCRs were compared with their homologues in Bombyx mori and Drosophila melanogaster. Our results suggest that GPCRs in different insect species may have evolved by a birth-and-death process. One of the differences among compared insects is the duplication of short neuropeptide F receptor and adipokinetic hormone receptors in P. xylostella and B. mori. Another divergence is the decrease in quantity and diversity of the stress-tolerance gene, Mth, in P. xylostella. The evolution by the birth-and-death process is probably involved in adaptation to the feeding behaviour, reproduction and stress responses of P. xylostella. Some of the genes identified in the present study could be potential targets for the development of novel pesticides.

Assessment of cerebral iron content in patients with Parkinson's disease by the susceptibility-weighted MRI.

OBJECTIVE: The overall goal of this study was to evaluate the usability of the susceptibility weighted imaging (SWI) in (1) assessment of iron deposition to enhance our ability to detect PD in the early phase and (2) in estimation of the degree of PD. PATIENTS AND METHODS: SWI scans were carried out in 54 patients with PD (18 patients with the Hoehn-Yahr scale < 1.5 and 36 patients with the Hoehn-Yahr stage > 1.5) and 40 control individuals. The phase values of the substantia nigra, red nucleus, caudate nucleus, putamen, and globus pallidus were measured on the corrected phase image. RESULTS: Compared with control individuals, patients with both the early and intermediate/ advanced stages of PD had significantly different phase values in the substantia nigra, red nucleus, caudate nucleus, putamen, and globus pallidus (all p < 0.05). The phase values of the substantia nigra and globus pallidus inversely correlated with the Hoehn-Yahr scale (respectively, r = -0.845, p < 0.05, and r = -0.868, p < 0.05). Weaker correlations were found between the phase values of red nucleus, caudate nucleus, putamen, and Hoehn-Yahr scale (red nucleus r = -0.543, caudate nucleus r = -0.620, p < 0.05, putamen r = -0.537). CONCLUSIONS: A semi-quantitative assessment of the iron content of the substantia nigra and globus pallidus with the help of SWI may be useful for early diagnosis of PD and evaluation of the degree of this disease.