Risk assessment of airborne agricultural pesticide exposure in humans in rural China.

Continuous exposure to airborne pesticides causes their gradual accumulation in the human body, eventually posing a threat to human health. To the best of our knowledge, risk assessment study of pesticide non-occupational exposure to residents in agricultural areas has not been conducted in China. In this study, air samples (gas and dust) were collected from inside and outside residences of seven households and an area near the field in a grain-growing area (wheat and maize rotation) for eight months, and the pesticides present were examined both qualitatively and quantitatively. Using a 95% confidence interval, 9 out of 16 pesticides were detected, namely acetamiprid, acetochlor, atrazine, flucarbazone-sodium, imidacloprid, methyldisulfuron-methyl, nicosulfuron-methyl, pendimethalin, and beta-cyhalothrin, and their safety was subsequently evaluated. The results showed that the inhalation exposure of households to beta-cyhalothrin exceeded the acceptable range in the first residential, and the excess lifetime cancer risk of acetochlor inhalation exposure in six households and area around the field exceeds 1E-6, which highlights the need to strengthen preventive screening for cancer risk.

Clinical value of [18F]AlF-NOTA-FAPI-04 PET/CT for assessing early-stage liver fibrosis in adult liver transplantation recipients compared with chronic HBV patients.

AIMS: To investigate the clinical value and performance of [18F]AlF-NOTA-FAPI-04 PET/CT in assessing early-stage liver fibrosis in liver transplantation (LT) recipients. METHODS: A prospective study including 17 LT recipients and 12 chronic Hepatitis B (CHB) patients was conducted. All patients received liver biopsy, transient elastography (TE), and [18F]AlF-NOTA-FAPI-04 PET/CT. On [18F]AlF-NOTA-FAPI-04 PET/CT scans, the liver parenchyma's maximum standardized uptake values (SUVmax) were measured. The receiver operating characteristic (ROC) curve analysis was applied to determine the diagnostic efficacy of [18F]AlF-NOTA-FAPI-04 PET/CT in early-stage liver fibrosis (S1-S2) compared with the diagnostic performance of TE. RESULTS: Among those 29 patients enrolled in this study, 15(51.7%) had fibrosis S0, 10(34.5%) had S1, and 4(13.8%) had S2, respectively. The SUVmax of patients with early-stage liver fibrosis was significantly higher than those without liver fibrosis in LT recipients and CHB patients (P = 0.004, P = 0.02). In LT recipients, a SUVmax cut-off value of 2.0 detected early-stage liver fibrosis with an AUROC of 0.92 (P = 0.006), and a liver stiffness measurements (LSM) score cut-off value of 8.2 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.80 (P = 0.012). In CHB patients, a SUVmax cut-off value of 2.7 detected early-stage liver fibrosis with an AUROC of 0.94 (P < 0.001) and an LSM scores cut-off value of 8.4 kPa diagnosed early-stage liver fibrosis with an AUROC of 0.91 (P < 0.001). CONCLUSION: [18F]AlF-NOTA-FAPI-04 PET/CT could be applied to evaluate early-stage liver fibrosis in LT recipients and CHB patients properly, with the potential additional advantages in monitoring and predicting complications after LT.

The effects of CPET-guided cardiac rehabilitation on exercise tolerance in older persons with CHD after PCI.

Prescribing appropriate exercise is an important means to improve the safety and efficacy of cardiac rehabilitation. Improper exercise may induce an increased cardiovascular risk in older persons with coronary heart disease. Cardiopulmonary exercise testing (CPET)-guided cardiac rehabilitation could be helpful for providing clinical evidence for cardiac rehabilitation therapy in older persons after percutaneous coronary intervention (PCI). We retrospectively included older persons who underwent PCI and cardiac rehabilitation based on CPET at the Cardiac Rehabilitation Center of Peking University Third Hospital from January 2014 to December 2019. Patients' baseline and follow-up clinical data were collected. A total of 403 older persons after PCI were included in the study. The mean age was 80.5 ± 4.3. The mean follow-up time was 12 ± 2 months. During the follow-up period, no significant exercise-related adverse events occurred, and the peak oxygen uptake (VO2peak) increased compared with baseline (15.5 ± 3.8 ml/min/kg vs. 17.3 ± 4.1 ml/min/kg). Among the 90 patients (22.2%) without exercise habits at baseline who started regular exercise during follow-up, the improvement in VO2peak was most significant, at 3.2 ± 0.4 ml/min/kg. Cardiac rehabilitation based on CPET improved exercise habits and exercise tolerance in older persons with coronary heart disease after PCI.

Case report: Fecal microbiota transplantation in refractory ankylosing spondylitis.

Ankylosing spondylitis (AS) is the prototype of a group of systemic inflammatory diseases referred to as spondyloarthritis. Comorbid inflammatory bowel disease and changed gut microbiota in AS have attracted attention to the influence of gut-joint axis and encouraged treating AS by targeting gut microbiota. Here we first reported a patient with refractory AS and comorbid ulcerative colitis (UC) who underwent three fecal microbiota transplantations (FMTs). Inadequate response to conventional treatments including tumor necrosis factor inhibitors impelled FMT as alternative therapy. Notable improvements in AS and UC accompanied with changed fecal microbiota were recorded at 1 week post-FMT1. Further recovery was found after the other two FMTs, and a roughly stable status was maintained in the follow-up period. More studies are needed to validate the effectiveness of FMT in AS and its mechanisms.

Symptoms compatible with Rome IV functional bowel disorder in patients with ankylosing spondylitis.

OBJECTIVES: To determine the frequency of symptoms meeting Rome IV functional bowel disorder (FBD) in patients with ankylosing spondylitis (AS), investigate factors associated with FBD symptoms, and assess whether having FBD symptoms might influence AS disease activity. METHODS: In this cross-sectional study, we enrolled 153 AS patients without known colonic ulcers and 56 sex- and age-matched controls to evaluate FBD (or its subtypes) symptoms. Disease characteristics were also evaluated in the AS group. RESULTS: Sixty (39.2%) of 153 AS patients had FBD symptoms, which were more prevalent than controls (23.2%). Besides, symptoms compatible with irritable bowel syndrome (IBS) and chronic diarrhoea were detected in 18 and 43 AS patients, respectively. For the AS group, multivariable logistic regression analyses showed that symptoms of FBD, IBS, and chronic diarrhoea were negatively associated with using non-steroidal anti-inflammatory drugs and positively associated with comorbid fibromyalgia, respectively. In exploration about the effects of FBD (or its subtypes) symptoms on AS disease activity by multivariable linear regression analyses, FBD symptoms and chronic diarrhoea had universal positive associations with assessments of AS disease characteristics, respectively. CONCLUSIONS: Patients with AS had frequent symptoms compatible with FBD, IBS, and chronic diarrhoea, proportions of which were lower in those with non-steroidal anti-inflammatory drug use. The improvement of FBD symptoms and chronic diarrhoea might be conducive to the disease status of AS patients.

RecurIndex assay as an aid for adjuvant chemotherapy decisions in HR-positive HER2-negative breast cancer patients.

Background: Adjuvant chemotherapy is a major adjuvant treatment modality for hormonal receptor (HR)-positive and HER2-negative early breast cancer, but only 2%-20% of patients derive practical benefits. How to balance its potential benefits and risks becomes a challenging clinical problem. The purpose of this study was to assess whether RecurIndex assay could serve as an aid for adjuvant chemotherapy decisions in Chinese patients with HR-positive HER2-negative early breast cancer. Methods: The tissue samples of pT1-2N0 HR-positive HER2-negative breast cancer from multiple centers were detected using RecurIndex assay, based on which the patients were assigned into low- and high-risk groups. The survival outcomes of low- and high-risk patients including those with and without adjuvant chemotherapy were compared, and the risk factors for recurrence and metastasis were identified. Results: Totally 445 patients were eligible for analysis. By contrast to high-risk patients, low-risk patients represented better 7-year recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS) rates. For low-risk patients, no significant differences were shown between those with and without adjuvant chemotherapy in 7-year RFS, DRFS and LRFS rates. These differences were also inapparent between high-risk patients with and without adjuvant chemotherapy. The multivariate model revealed high-risk patients had a significantly elevated risk of recurrence and metastasis than those at low risk. Conclusion: HR-positive HER2-negative early breast cancer patients at low risk stratified by RecurIndex assay might be exempt from adjuvant chemotherapy. Whether adjuvant chemotherapy may derive survival benefits for high-risk patients still needs larger cohorts to verify.

Complete Mitogenomes of Polypedates Tree Frogs Unveil Gene Rearrangement and Concerted Evolution within Rhacophoridae.

New developments in sequencing technology and nucleotide analysis have allowed us to make great advances in reconstructing anuran phylogeny. As a clade of representative amphibians that have radiated from aquatic to arboreal habitats, our understanding of the systematic status and molecular biology of rhacophorid tree frogs is still limited. We determined two new mitogenomes for the genus Polypedates (Rhacophoridae): P. impresus and P. mutus. We conducted comparative and phylogenetic analyses using our data and seven other rhacophorid mitogenomes. The mitogenomes of the genera Polypedates, Buergeria, and Zhangixalus were almost identical, except that the ATP8 gene in Polypedates had become a non-coding region; Buergeria maintained the legacy "LTPF" tRNA gene cluster compared to the novel "TLPF" order in the other two genera; and B. buergeri and Z. dennysi had no control region (CR) duplication. The resulting phylogenetic relationship supporting the above gene rearrangement pathway suggested parallel evolution of ATP8 gene loss of function (LoF) in Polypedates and CR duplication with concerted evolution of paralogous CRs in rhacophorids. Finally, conflicting topologies in the phylograms of 185 species reflected the advantages of phylogenetic analyses using multiple loci.

Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer.

PURPOSE: We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance. METHODS: PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing. RESULTS: Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days, p = 2.28 × 10-13). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness- and epithelial-mesenchymal transition (EMT)-related gene sets were found to be upregulated, whereas liver development- and liver specific molecule-related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis. CONCLUSIONS: HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.

Clinical Outcome of Surgical Hip Dislocation Combined with Impacting Bone Grafts and Implanting Iliac Bone Flaps in the Treatment of Osteonecrosis of the Femoral Head: A Mid-term Retrospective Study.

OBJECTIVE: To report the medium-term outcomes of surgical hip dislocation (SHD) combined with impacting bone grafts and implanting iliac bone flaps in the treatment of osteonecrosis of the femoral head (ONFH) and to define the indications for this treatment. METHODS: This was a single-center retrospective study. In total, 64 patients (70 hips) with ONFH treated from January 2014 to December 2017 were included in this study. There were 51 males and 13 females aged 18-55 years with an average age of 32 years. All patients underwent surgery for SHD combined with impacting bone grafts and implanting iliac bone flaps. Preoperative and postoperative clinical outcomes were assessed. The clinical outcome was assessed using the Harris hip score (HHS) and the conversion rate of total hip arthroplasty (THA). Univariate and multivariate logistic regression analyses were performed to identify risk factors affecting the clinical outcome. Kaplan-Meier (K-M) analysis was applied to calculate the survival rate of the femoral head. RESULTS: At the last follow-up (60 ± 15.08 months), the HHS was excellent for 41 hips, good for 17 hips, fair for three hips, and poor for nine hips. All nine hips with poor HHS underwent THA, including five in the first 2 years following the index surgery and four between three and 5 years. The conversion rate of total hip arthroplasty was 12.86%. Univariate and multivariate logistic regression analyses showed that the duration of hip pain and JIC classification type were significantly associated with clinical outcomes. Elderly age and advanced ONFH stage tended to lead to worse surgical outcomes. The overall survival rate of JIC classification type C1 and duration of pain ≤6 months was 98.1% and 97.8% at 72 months, respectively, as estimated by the Kaplan-Meier method. CONCLUSION: Surgical hip dislocation combined with impacting bone grafts and implanting iliac bone flaps in the treatment of ONFH had a good mid-term clinical outcome, especially for patients with retention of the lateral column of the femoral head and hip pain less than 1 year.

A Retrospective Study on the Clinicopathologic Characteristics and Outcomes of 179 Cases of Synchronous and Metachronous Bilateral Breast Cancer in China.

OBJECTIVE: To investigate the clinicopathologic characteristics and outcome of bilateral breast cancer (BBC) in the Chinese population. METHODS: A retrospective study was conducted on 7797 cases with primary breast cancer, including 7618 cases of unilateral breast cancer (UBC) and 179 cases of BBC. Among the latter, there were 108 cases of synchronous BBC (SBBC) and 71 cases of metachronous BBC (MBBC). RESULTS: In the present study, the incidence of SBBC and MBBC are 1.39% and 0.91% among the general population, respectively. In comparison of UBC and BBC, SBBC and MBBC, there are significant differences in the common clinicopathological characteristics, such as pathologic stage, hormone receptor (HR) status and molecular type. In respect of the surgical treatment of BBC, 49.72% of the patients chose mastectomy. The 3-year disease free survival (DFS) for SBBC and MBBC are 94.4% and 96.9%, respectively. There is no difference in the overall survival (OS) and DFS between SBBC and MBBC. The histological grade and type of surgery on tumors of both sides are important influencing factors of DFS in the BBC patients. CONCLUSION: There are statistical differences in the clinicopathological characteristics and outcomes between SBBC and MBBC among the Chinese population. Therefore, the treatment of BBC patients should be individualized.

Survival-associated N6-adenosine methyltransferase signatures in lung squamous cell carcinoma and clinical verification.

BACKGROUND: N6-methyladenine (m6A) is the most common modification of mRNA and IncRNA in higher organisms. m6A has been confirmed to be related to the formation and progression of tumors and m6A-related genes can be used as prognostic biomarkers in a variety of tumors. However, there have been no similar studies on lung squamous cell carcinoma. The main purpose of this study was aimed to explore the differential expression of m6A-related genes in lung squamous cell carcinoma tissues and its relationship with patient clinical prognosis. METHODS: We integrated three m6A writers that catalyze the methylation of adenine on mRNA molecules. The training set including 501 patients with LUSC was collected from The Cancer Genome Atlas (TCGA) database and the test set including 181 patients with LUSC was collected from the Gene Expression Omnibus (GEO) database. Based on the expression level of the m6A methylase gene, we established a tumor subgroup and risk-prognosis model to quantify the risk index and long-term patient prognosis, which were confirmed by principal component analysis (PCA) and receiver operating characteristic (ROC) curve analysis. After lung squamous cell carcinoma tissue specimens were obtained during surgery, immunohistochemistry (IHC) was used to verify the results in vitro. RESULTS: The results of the study showed that the expression of the three m6A methylases in tumor tissues and normal tissues was significantly different (P < 0.05). The survival-prognostic model based on METTL3 gene expression showed better predictive performance (AUC: 0.706). Patients in the high-risk and low-risk groups exhibited significant differences in terms of survival time and 5-year and 10-year survival rates. Immunohistochemistry revealed that patients with high METTL3 expression exhibited a longer survival time than those with low METTL3 expression. CONCLUSIONS: Our study showed that the molecular phenotype based on the expression of METTL3 may be an independent risk factor affecting the prognosis of lung squamous cell carcinoma. These findings not only prove the important role of m6A methylase in lung squamous cell carcinoma, but are also expected to provide more accurate prognostic assessment and individualized treatment for patients with lung squamous cell carcinoma.

SH3BGRL3, transcribed by STAT3, facilitates glioblastoma tumorigenesis by activating STAT3 signaling.

Glioblastoma (GBM) is the most aggressive tumors of the central nervous system. Here, we report that SH3 binding glutamic acid-rich protein like 3 (SH3BGRL3) was extremely highly expressed in GBM and glioma stem cells. SH3BGRL3 high expression associates with worse survival of GBM patients. Functionally, Targeting SH3BGRL3 obviously impairs GSCs self-renewal in vitro. Most importantly, we first report that SH3BGRL3 is a direct transcriptional target gene of signal transducer and activator of transcription 3 (STAT3) and thereby activating STAT3 signaling in turn. Additionally, forced expression of the constitutively activated STAT3 (STAT3-C) rescued GSCs self-renewal inhibited by SH3BGRL3 silencing. Collectively, we first identified a critical positive feedback loop between SH3BGRL3 and STAT3, which facilitates the tumorigenic potential of GBM.

[Cadmium Accumulation Characteristics and Impacting Factors of Different Rice Varieties Under Paddy Soils with High Geological Backgrounds].

The cadmium (Cd) accumulation characteristics of seven rice varieties (Ningliangyou 1, Y Liangyou 1, Shenliangyou, Tailiangyou, Yuejingsimiao, Youzhanbahao, and Huang Huazhan) were studied by pot-culture experiments in two paddy soils (Maling, Yunbiao) with different high geological backgrounds, and the possible impacting factors were explored. The results indicated that:① The grain Cd contents of the seven rice varieties grown in the two soils did not exceed the national food safety standard (GB 2762-2017), and the grain Cd content of Shengliangyou was the lowest; ② The grain Cd content of the seven rice varieties planted in the soil of Maling was higher than those of Yunbiao; ③ The redundancy analysis revealed that the accumulation of Cd in grains was influenced by the plant height, surface area of root, total cadmium in the soil, and EC and Eh of the soil during the heading stage. The correlation analysis indicated that the leading impacting factor of the grain Cd accumulation varied. In the Maling soil, the grain Cd content was primarily related to the rice root length, while it was related to the aboveground rice biomass in the Yunbiao soil.

SH3BGRL2 functions as a crucial tumor suppressor in glioblastoma tumorigenesis.

Glioblastoma is the most common and severe primary intrinsic tumor of the central nervous system. Glioblastoma harbors glioma stem cells (GSCs) as it not only possesses self-renewal and differentiation properties but also accounts for significant chemotherapy resistance and recurrence. Thus, targeting GSCs may be essential in overcoming the resistance and recurrence thereby improving GBM treatment. However, the underlying mechanism to sustain GSCs remains largely unknown. Here, we report that SH3 domain binding glutamate-rich protein like 2 (SH3BGRL2) is weakly expressed in glioblastoma multiforme (GBM) and isocitrate dehydrogenase1 (IDH1) wildtype GBM and correlated with glioma patients' poor prognosis. Moreover, ectopic expression of SH3BGRL2 significantly inhibited GBM cell growth, migration, and GSCs self-renewal in vitro as well as tumor growth in vivo. Additionally, we found that SH3BGRL2 suppressed SOX2 and CD133 expression, which are key regulators involved in GSCs self-renewal. Collectively, our findings shed additional light on SH3BGRL2 has potential to serve as a biomarker and a potent therapeutic target for patients with glioma.

SH3GL3 acts as a novel tumor suppressor in glioblastoma tumorigenesis by inhibiting STAT3 signaling.

Glioblastoma (GBM) is the most severe malignant tumors of the central nervous system. Glioblastoma stem cells (GSCs) are considered to account for tumor initiation, therapeutic resistance, and tumor relapse. Yet the underlying mechanisms of GSC stemness maintenance remain largely unknown. Abnormal activation of STAT3 signaling is required for GBM tumorigenesis and GSC self-renewal. In this study, we provide evidence that SH3GL3 was weakly expressed in GBM and its high expression correlated with a favorable prognosis for GBM patients. Ectopic of SH3GL3 expression considerably inhibits GBM cell malignant behaviors, including GBM cell proliferation, migration as well as GSCs self-renewal ability. Mechanistically, we first found that SH3GL3 interacts with STAT3, which thereby inhibiting STAT3 nuclear localization. Overexpression of constitutively activated (STAT3-C) restored the growth, migration and self-renewal ability impaired by overexpression of SH3GL3. Together, our work shed insight on a critical regulatory mechanism mediated by SH3GL3 to decrease the stem cell-like property and tumorigenic potential.

HER2 immunohistochemistry staining positivity is strongly predictive of tumor response to neoadjuvant chemotherapy in HER2 positive breast cancer.

BACKGROUND: The current recommendation is to reflex test HER2 immunohistochemistry (IHC) equivocal breast cancer cases with fluorescence in situ hybridization (FISH) analysis. Either IHC 3+ or FISH positive cancers are considered HER2 positive (HER2+) and treated with HER2 targeted therapy. This study examined the predictive value of HER IHC or FISH positivity in tumor response to HER2 targeted therapy. METHODS: Biopsies of 76 HER2+ breast cancer cases were evaluated. All patients were treated with neoadjuvant HER2 targeted therapy and chemotherapy. Tumor response was evaluated on the excisional specimens. Cancers with complete pathologic response (pCR) or MD Anderson residual cancer burden-I (RCB-I) were classified as responders and cancers with RCB-II/III as non-responders. Clinicopathologic parameters were correlated with response. RESULTS: In univariate analysis, small tumor size, low nuclear grade, high Ki67, HER2 IHC 3+, homogenous strong HER2 IHC staining, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with pCR/RCB-I. In multivariate analysis, homogenous strong HER2 IHC staining pattern was significantly associated with pCR/RCB-I. The receiver operating characteristics (ROC) model showed either high HER2/CEP17 ratio or HER2 copy number individually was predictive of tumor response. CONCLUSION: HER2 IHC staining pattern is significantly associated with tumor response to neoadjuvant chemotherapy, reiterating the importance of HER2 IHC evaluation. The ROC model shows either high HER2/CEP17 ratio or high HER2 copy number individually is predictive of tumor response to neoadjuvant HER2 targeted therapy in HER2+ breast cancer.

Evaluation of PD-L1, tumor-infiltrating lymphocytes, and CD8+ and FOXP3+ immune cells in HER2-positive breast cancer treated with neoadjuvant therapies.

BACKGROUND: The tumor immune microenvironment plays a critical role in the prognosis and outcome of breast cancers. This study examined the role of tumor-infiltrating lymphocytes (TILs), CD8+, FOXP3+ lymphocytes, PD-L1 expression, and other clinicopathological parameters in HER2+ breast cancer and correlate with tumor response to neoadjuvant therapy. METHODS: We included 173 HER2+ patients treated with neoadjuvant HER2-targeted chemotherapy regimens from 2010 to 2016. 67 cases had biopsy blocks to evaluate TIL, CD8, FOXP3, and PD-L1 immunohistochemistry staining. Tumors were classified as pCR vs non-pCR group. Clinicopathological parameters, TIL, CD8+ and FOXP3+ cell count, and PD-L1 expression were correlated with pCR rate. RESULTS: Univariate analyses showed that pCR rate was significantly correlated with low PR, low ER, high Ki-67, high FOXP3, HER2 IHC3+ , high HER2 ratio and copy number. By multivariate analysis, Ki-67 was the only variable significantly correlated with pCR. PD-L1 expression was detected in 9.2% cases. TIL hotspot has a non-significant correlation with pCR rate (p = 0.096). CONCLUSIONS: High Ki-67 is a strong predictor for pCR in HER2+ breast cancer. TIL and FOXP3 T cells may play a role in tumor response in HER2+ cancer. PD-L1 is expressed in a subset of HER2+ breast cancer, supporting a role of immunotherapy in treating a subset of HER2+ breast cancers. The role of PD-L1, TIL, and other markers of immunogenicity as predictors of response to neoadjuvant chemotherapy in HER2+ breast cancer should be further evaluated.

Inflammatory Demyelinating Pseudotumor With Liver Dysfunction: IgG4 Related Disease With Primary Biliary Cholangitis.

Immunoglobulin G4 related disease (IgG4-RD) is a recently recognized immune-mediated disease which is far from understanding. A case of inflammatory demyelinating pseudotumor had been confirmed as IgG4-RD according to pathology features and clinical context. Combined with liver dysfunction, IgG4 related sclerotic cholangitis was suspected. However, primary biliary cholangitis was finally diagnosed by immune marks and histopathological findings. This is the first report in which mass lesions in the brain parenchyma were caused by IgG4-RD while liver dysfunction was due to primary biliary cholangitis. The clinical features of IgG4-RD are miscellaneous, and the accumulation of case reports might enrich clinicians experience and broaden their horizons about this condition.

Pyrrolo [3,4-b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2.

Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes of breast cancer; however, it lacks effective targeted therapies clinically. In this study, we found FZU-0038-056, a novel compound derived from last-stage functionalization of tetrahydro-ß-carboline scaffold, showed the most potent anti-cancer activity against TNBC cells among the 42 synthesized derivatives. We found FZU-0038-056 significantly induces apoptosis in HCC1806 and HCC1937 TNBC cells. FZU-0038-056 reduces the expression levels of several anti-apoptosis proteins, including Bcl-2, Mcl-1 and XIAP. Furthermore, we found FZU-0038-056 induces apoptosis partially through inhibiting the expression of Bcl-2. Finally, we found FZU-0038-056 significantly suppresses HCC1806 xenograft tumor growth in nude mice without affecting their body weight. Therefore, FZU-0038-056 has the potential to be a new anticancer agent for treating human TNBC.

Suppression of KIF3A inhibits triple negative breast cancer growth and metastasis by repressing Rb-E2F signaling and epithelial-mesenchymal transition.

Triple negative breast cancer (TNBC) displays higher heterogeneity, stronger invasiveness, higher risk of metastasis and poorer prognosis compared with major breast cancer subtypes. KIF3A, a member of the kinesin family of motor proteins, serves as a microtubule-directed motor subunit and has been found to regulate early development, ciliogenesis and tumorigenesis. To explore the expression, regulation and mechanism of KIF3A in TNBC, 3 TNBC cell lines, 98 cases of primary TNBC and paired adjacent tissues were examined. Immunohistochemistry, real-time PCR, western blot, flow cytometry, short hairpin RNA (shRNA) interference, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation techniques, transwell assays, scratch tests, and xenograft mice models were used. We found that KIF3A was overexpressed in TNBC and such high KIF3A expression was also associated with tumor recurrence and lymph node metastasis. Silencing of KIF3A suppressed TNBC cell proliferation by repressing the Rb-E2F signaling pathway and inhibited migration and invasion by repressing epithelial-mesenchymal transition. The tumor size was smaller and the number of lung metastatic nodules was lower in KIF3A depletion MDA-MB-231 cell xenograft mice than in the negative control group. In addition, KIF3A overexpression correlated with chemoresistance. These results suggested that high expression of KIF3A in TNBC was associated with the tumor progression and metastasis.