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The effect of the submergence depth of surface aerator on the structure of flow field, aeration gas-volume-fraction distribution, and the ability to move fluid in an oxidation ditch (OD) was studied by using an experimentally validated computational fluid dynamics model (in FLUENT6.3.26). The gas–liquid two-phase model with the three-dimensional (3D) renormalized group k–ε turbulence model was used to describe the gas–liquid two-phase flows in ODs; the pressure-implicit with splitting of operators algorithm was used to solve the velocity and pressure; and the volume of fluid method was used to simulate the water surface. The concept of the submergence depth ratio was introduced to describe the submergence depth of the surface aerator in the OD. With the different submergence depth ratios of 1/4, 1/3, 1/2, and 3/4, the velocity fields and gas content distributions were computed, by which the optimal submergence depth ratio from 1/3 to 1/2 of the surface aerator was obtained. The research result has a certain reference for reducing sludge deposit and prolonging liquid-gas mixing time in an OD. [ABSTRACT FROM AUTHOR]

In the 1+1D ultralocal lattice Hamiltonian for staggered fermions with a finite-dimensional Hilbert space, there are two conserved, integer-valued charges that flow in the continuum limit to the vector and axial charges of a massless Dirac fermion with a perturbative anomaly. Each of the two lattice charges generates an ordinary U(1) global symmetry that acts locally on operators and can be gauged individually. Interestingly, they do not commute on a finite lattice and generate the Onsager algebra, but their commutator goes to zero in the continuum limit. The chiral anomaly is matched by this non-Abelian algebra, which is consistent with the Nielsen-Ninomiya theorem. We further prove that the presence of these two conserved lattice charges forces the low-energy phase to be gapless, reminiscent of the consequence from perturbative anomalies of continuous global symmetries in continuum field theory. Upon bosonization, these two charges lead to two exact U(1) symmetries in the XX model that flow to the momentum and winding symmetries in the free boson conformal field theory.

We show that the standard 1+1D Z_{2}×Z_{2} cluster model has a noninvertible global symmetry, described by the fusion category Rep(D_{8}). Therefore, the cluster state is not only a Z_{2}×Z_{2} symmetry protected topological (SPT) phase, but also a noninvertible SPT phase. We further find two new commuting Pauli Hamiltonians for the other two Rep(D_{8}) SPT phases on a tensor product Hilbert space of qubits, matching the classification in field theory and mathematics. We identify the edge modes and the local projective algebras at the interfaces between these noninvertible SPT phases. Finally, we show that there does not exist a symmetric entangler that maps between these distinct SPT states.

Objective: The incidence of recurrent hernia after radical resection of prostate cancer is high, so this article discusses the incidence and risk factors of inguinal hernia after radical resection of prostate cancer., Methods: This case control study was conducted in The First People's Hospital of Huzhou clinical data of 251 cases underwent radical resection of prostate cancer in this hospital from March 2019 to May 2021 were retrospectively analyzed. According to the occurrence of inguinal hernia, the subjects were divided into study group and control group, and the clinical data of each group were statistically analyzed, Multivariate Logistic analysis was performed to find independent influencing factors for predicting the occurrence of inguinal hernia. The Kaplan-Meier survival curve was drawn according to the occurrence and time of inguinal hernia., Results: The overall incidence of inguinal hernia after prostate cancer surgery was 14.7% (37/251), and the mean time was 8.58 ± 4.12 months. The average time of inguinal hernia in patients who received lymph node dissection was 7.61 ± 4.05 (month), and that in patients who did not receive lymph node dissection was 9.16 ± 4.15 (month), and there was no significant difference between them (P > 0.05). There were no statistically significant differences in the incidence of inguinal hernia with age, BMI, hypertension, diabetes, PSA, previous abdominal operations and operative approach (P > 0.05), but there were statistically significant differences with surgical method and pelvic lymph node dissection (P < 0.05). The incidence of pelvic lymph node dissection in the inguinal hernia group was 24.3% (14/57), which was significantly higher than that in the control group 11.8% (23/194). Logistic regression analysis showed that pelvic lymph node dissection was a risk factor for inguinal hernia after prostate cancer surgery (OR = 0.413, 95%Cl: 0.196-0.869, P = 0.02). Kaplan-Meier survival curve showed that the rate of inguinal hernia in the group receiving pelvic lymph node dissection was significantly higher than that in the control group (P < 0.05)., Conclusion: Pelvic lymph node dissection is a risk factor for inguinal hernia after radical resection of prostate cancer., (© 2024. The Author(s).)

We derive model-independent quantization conditions on the axion couplings (sometimes known as the anomaly coefficients) to the standard model gauge group [SU(3)×SU(2)×U(1)&#95;{Y}]/Z&#95;{q} with q=1, 2, 3, 6. Using these quantization conditions, we prove that any QCD axion model to the right of the E/N=8/3 line on the |g&#95;{aγγ}|-m&#95;{a} plot must necessarily face the axion domain wall problem in a postinflationary scenario. We further demonstrate the higher-group and noninvertible global symmetries in the standard model coupled to a single axion. These generalized global symmetries lead to universal bounds on the axion string tension and the monopole mass. If the axion were discovered in the future, our quantization conditions could be used to constrain the global form of the standard model gauge group.

Background: Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8)., Methods: CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed., Results: From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified., Conclusions: The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted., Trial Registration Number: NCT03414983., Competing Interests: Competing interests: H-JL reports consulting or advisory roles for Bayer, Bristol Myers Squibb, GlaxoSmithKline, Merck Serono, and Roche; honoraria from Bayer, Boehringer Ingelheim, Fulgent Genetics, GlaxoSmithKline, G1 Therapeutics, Isofol Medical, Jazz Pharmaceuticals, Merck Serono, Oncocyte, and Roche; travel, accommodations, and expenses from Bayer and Merck Serono. AP reports equity in C2i Genomics; advisor/consultant roles for Eli Lilly, Pfizer, Inivata, Biofidelity, Natera, Checkmate Pharmaceuticals, FMI, Guardant, AbbVie, Bayer, and Taiho; served on the DSMC for a Roche study; and has received research funding to the institution from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, Bristol Myers Squibb, Mirati Therapeutics, Novartis, Genentech, Natera, and Daiichi Sankyo. DRS reports consulting or advisory roles for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Curio Science, EMD Serono, Evelo Therapeutics, Evidera, Exelixis, Genentech/Roche, GlaxoSmithKline, Intellisphere, Ipsen, Janssen, Jazz Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron, Sanofi/Aventis, and Takeda; leadership roles at ASCO; travel, accommodations, and expenses from AstraZeneca, Genentech, and Novartis; and has received research funding to institution from Aeglea Biotherapeutics, Agios, Apollomics, Arcus Biosciences, Arrys Therapeutics, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Celgene, Celldex, Clovis Oncology, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Immunogen, Incyte, Ipsen, Janssen Oncology, Kronos Bio, Eli Lilly, Loxo, Macrogenics, MedImmune, Merck, Molecular Partners, Molecular Templates, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics Inc., Transgene, University of Texas Southwestern Medical Center – Simmons Cancer Center, and Verastem. ALC reports honoraria from Amgen; and has provided expert testimony for the Department of Justice. TY reports honoraria from Chugai Pharmaceuticals, Merck, Bayer Yakuhin, Ono Pharmaceutical Co., Ltd, Eli Lilly, and Taiho Pharmaceuticals; and research funding from Chugai Pharmaceuticals, Merck Sharp & Dohme Corporation, Daiichi Sankyo, Parexel, Ono Pharmaceutical Co., Ltd, Taiho Pharmaceuticals, Amgen, and Sanofi. EE reports honoraria from Servier, Array Biopharma, Roche, Bristol Myers Squibb, Merck Serono, and Sanofi/Aventis; honoraria from Boehringer Ingelheim, Amgen, GlaxoSmithKline, AbbVie/Genetech, Novartis, MSD, and AstraZeneca (to institution); consulting and advisory roles for Array BioPharma, Bristol Myers Squibb, Roche, Servier, Sanofi, Amgen, Merck Serono, and Bayer; research funding from Merck Serono and Amgen; and research funding (to institution) from Sanofi/Aventis, Servier, Bristol Myers Squibb, Array BioPharma, Roche, Pierre Fabre, and MedImmune; and travel and accommodations from Servier. DD reports consulting roles for Bayer, Promega, Array Biopharma, Eli Lilly, and Pfizer; and research funding from Merck, Bristol Myers Squibb, Genentech, Revolution Medicines, Millenium Pharmaceuticals, and Bayer. EC reports honoraria from Eisai and Bayer; and research funding from Bristol Myers Squibb, Merck, Novartis, Boston Biomedical, AstraZeneca, and Zymeworks. AM reports consulting or advisory roles for QED Therapeutics; honoraria from Eisai; and research funding from Taiho Pharmaceuticals. EB-B was an employee of Bristol Myers Squibb at the time of the study and reports consulting or advisory roles for Bristol Myers Squibb, Fennec Pharmaceuticals, Green3Bio, Geistlich Pharma, Oncternal Therapeutics, and Shasqi Inc; leadership roles in Catalyst Clinical Research; travel, accommodations, and expenses from Geistlich Pharma; and stock and other ownership interests in Oncternal Therapeutics and Catalyst Clinical Research. TK reports being an employee of Bristol Myers Squibb. DC, ABH, and JY report being employees of and owning stock in Bristol Myers Squibb. JT reports consulting roles for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; stocks from Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER). All other authors report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There are four solid tumors with common screening options in the average-risk population aged 21 to 75 years (breast, cervical, colorectal, and, based on personalized risk assessment, prostate), but many cancers lack recommended population screening and are often detected at advanced stages when mortality is high. Blood-based multi-cancer early detection tests have the potential to improve cancer mortality through additional population screening. Reported here is a post-hoc analysis from the third Circulating Cell-free Genome Atlas substudy to examine multi-cancer early detection test performance in solid tumors with and without population screening recommendations and in hematologic malignancies. Participants with cancer in the third Circulating Cell-free Genome Atlas substudy analysis were split into three subgroups: solid screened tumors (breast, cervical, colorectal, prostate), solid unscreened tumors, and hematologic malignancies. In this post hoc analysis, sensitivity is reported for each subgroup across all ages and those aged ⩾50 years overall, by cancer, and by clinical cancer stage. Aggregate sensitivity in the solid screened, solid unscreened, and hematologic malignancy subgroups was 34%, 66%, and 55% across all cancer stages, respectively; restricting to participants aged ⩾50 years showed similar aggregate sensitivity. Aggregate sensitivity was 27%, 53%, and 60% across stages I to III, respectively. Within the solid unscreened subgroup, aggregate sensitivity was >75% in 8/18 cancers (44%) and >50% in 13/18 (72%). This multi-cancer early detection test detected cancer signals at high (>75%) sensitivity for multiple cancers without existing population screening recommendations, suggesting its potential to complement recommended screening programs.Clinical trial identifier: NCT02889978.

One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori ( H. pylori ) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori . Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xi, Zhang, Luo, Gan, Liu, Shao and Mao.)

In gauge theory, it is commonly stated that time-reversal symmetry only exists at θ=0 or π for a 2π-periodic θ angle. In this Letter, we point out that in both the free Maxwell theory and massive QED, there is a noninvertible time-reversal symmetry at every rational θ angle, i.e., θ=πp/N. The noninvertible time-reversal symmetry is implemented by a conserved, antilinear operator without an inverse. It is a composition of the naive time-reversal transformation and a fractional quantum Hall state. We also find similar noninvertible time-reversal symmetries in non-Abelian gauge theories, including the N=4 SU(2) super Yang-Mills theory along the locus |τ|=1 on the conformal manifold.

Background: Liver cancer is a malignant tumor with high morbidity and mortality. Transcatheter arterial chemoembolization (TACE) is the main method for surgically unresectable liver cancer. In recent years, drug-loaded microspheres have been gradually applied in TACE technology. There are some controversies about the therapeutic effects of drug-loaded microspheres TACE (D-TACE) and traditional TACE., Aim: To explore the short-term efficacy of D-TACE and traditional TACE in the treatment of advanced liver cancer., Methods: The clinical data of 73 patients with advanced liver cancer admitted to the First and Sixth Medical Centers of Chinese PLA General Hospital from January 2017 to October 2019 were retrospectively analyzed. Among them, 15 patients were treated with D-TACE, and 58 patients were treated with traditional TACE. Clinical baseline characteristics, perioperative laboratory indices, postoperative adverse reactions and postoperative complications were compared between the two groups., Results: There was no statistical difference between the two groups for the postoperative response: The highest postoperative body temperature of the drug-loaded microsphere group was 38.0 ± 0.9℃ and the postoperative highest body temperature of the traditional TACE group was 38.3 ± 0.7℃ ( t = -1.414, P = 0.162). For the 24 h postoperative nausea and vomiting after surgery in terms of scoring and postoperative pain scores, the traditional TACE group was higher than the drug-loaded microsphere group ( χ 2 = 14.33, P = 0.014; χ 2 = 32.967, P = 0.000) and the two groups had significant statistical differences. The disease control rate at 3 mo after treatment in the drug-loaded microsphere group was 60% and the disease control rate at 3 mo after treatment in the traditional TACE group was 75.9% ( χ 2 = 4.091, P = 0.252). There was no statistical difference between the two groups of data. During the follow-up period, the number of interventional treatments received was once in the drug-loaded microsphere group and the traditional TACE group received an average of 1.48 treatments ( χ 2 = 10.444 P = 0.005). There was a statistical difference between the two groups., Conclusion: Compared with traditional TACE, D-TACE may have some advantages in the treatment of advanced hepatocellular carcinoma with a large tumor load in the short term, but the long-term clinical efficacy needs additional follow-up studies. In addition, compared with the traditional group, the patients in the drug-loaded microsphere group had better subjective tolerance and could reduce the number of interventional treatments. Therefore, D-TACE is worthy of clinical promotion., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

We identify infinitely many noninvertible generalized global symmetries in QED and QCD for the real world in the massless limit. In QED, while there is no conserved Noether current for the U(1)&#95;{A} axial symmetry because of the Adler-Bell-Jackiw anomaly, for every rational angle 2πp/N, we construct a conserved and gauge-invariant topological symmetry operator. Intuitively, it is a composition of the axial rotation and a fractional quantum Hall state coupled to the electromagnetic U(1) gauge field. These conserved symmetry operators do not obey a group multiplication law, but a noninvertible fusion algebra. They act invertibly on all local operators as axial rotations, but noninvertibly on the 't Hooft lines. We further generalize our construction to QCD, and show that the coupling π^{0}F∧F in the effective pion Lagrangian is necessary to match these noninvertible symmetries in the UV. Therefore, the conventional argument for the neutral pion decay using the ABJ anomaly is now rephrased as a matching condition of a generalized global symmetry.

Background: Renal cell carcinoma (RCC) with Xp11.2 translocation/TFE3 gene fusion is a rare and distinct subtype of RCC that is classified under tumors with translocation of the microphthalmia-associated transcriptional factor., Case Summary: We report an adult case of Xp11.2 translocation advanced RCC with metastasis (T3aN1M1), after targeted treatment, alcohol ablation, and transarterial chemoembolization, who eventually underwent successful surgical excision. No recurrence or transfer was seen within one year, and the survival period was more than 3 years. A review of the relevant literature was conducted to improve our understanding of the pathogenesis, epidemiology, clinical manifestations, diagnosis, differential diagnosis, treatment, and other aspects of the disease., Conclusion: Transarterial chemoembolization and ablation did not achieve the desired tumor reduction in this patient, but had a significant effect on reducing intraoperative bleeding and inhibiting tumor activity., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Pulmonary bronchiolar adenoma (BA) is a rare lung tumour, it is unclear whether BA can develop into a malignancy. We presented five cases of BA-like tumour with monolayered components. This type of tumour may represent the malignant transformation of BA. Histologically, these tumours showed acinar and lepidic growth patterns. The acinar components were well-differentiated. The glandular tumour cells in these tumours contained cuboidal to columnar cells resembling type II pneumocytes or club (Clara) cells. A small number of mucinous cells were found in two cases. A few scattered ciliated cells were detected in three cases. The ciliated cells only existed in the bilayered components. The basal cells were highlighted by CK5/6 and p40 in a partial region of the tumour rather than in the entire tumour. The glandular tumour cells, including those in the bilayered component, were diffusely positive for TTF-1 and napsin-A. EGFR Exon19 deletions were found in four cases, and BRAF V600E mutation was found in one case. These BA-like tumours have biphasic morphological and molecular characteristics of BA and lung adenocarcinoma, suggesting distal-type BA may develop into a malignancy. More cases should be studied and especially cases with metastasis should be searched to further prove the malignant transformation., Competing Interests: Conflict of interest Authors declare that there is no conflict of interest in the study., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Objective: To investigate the expression intensity of carbonic anhydrase IX (CA-IX) in bladder urothelial carcinoma and its predictive value for the recurrence after transurethral resection of bladder tumor., Methods: A retrospective analysis was made of 194 specimens who underwent transurethral resection of bladder tumors in our hospital from January 2014 to January 2016 and completed follow-up. The expression intensity of CA-IX and the clinical data of the patients were analyzed, and the subjects were divided into positive group and negative group according to the expression intensity of CA-IX. The age, gender, T stage, degree of differentiation, tumor number, tumor diameter, recurrence of each group was analyzed. Logistic univariate and multivariate analysis was used successively to find independent influencing factors for predicting the recurrence of bladder urothelial carcinoma after resection. The Kaplan-Meier survival curve was drawn according to the relationship between CA-IX expression intensity and postoperative recurrence., Results: The positive expression rates of CA-IX in bladder urothelial carcinomas were 68.1% (132/194). The positive expression of CA-IX had no statistical significance with age, gender and tumor diameter (P > 0.05), while the positive expression of CA-IX had statistical significance with tumor T stage, tumor differentiation, tumor number and recurrence (P < 0.05); Logistic regression analysis showed that clinical T stage, tumor differentiation, tumor number, and CA-IX expression intensities were independent risk factors for predicting recurrence of bladder urothelial carcinoma after resection (P < 0.05); There were 59 cases of recurrence in the positive expression of CA-IX group, with a recurrence rate of 44.69% (59/132), and 17 cases of recurrence in the negative expression group, with a recurrence rate of 27.41% (17/62). The mean recurrence time of CA-IX positive group was 29.93 ± 9.86 (months), and the mean recurrence time of CA-IX negative group was 34.02 ± 12.44 (months). The Kaplan-Meier survival curve showed that the recurrence rate and recurrence time of patients with positive expression of CA-IX in bladder urothelial carcinomas were significantly higher than those of patients with negative expression of CA-IX., Conclusion: CA-IX is highly expressed in bladder urothelial carcinoma, is a good tumor marker, and can be used as a good indicator for predicting the recurrence of bladder urothelial carcinoma after transurethral resection of bladder tumor., (© 2022. The Author(s).)

Purpose: Type 2 diabetes mellitus (T2DM) is among the risk factors for the occurrence and development of cancer. Metformin is a potential anticancer drug. Epidermal growth factor receptor (EGFR) plays an important role in the progression of oral squamous cell carcinoma(OSCC), but the relationship between metformin and EGFR expression in OSCC remains unclear., Methods: This study involved the immunohistochemical detection of EGFR expression in cancer tissues of patients with T2DM and OSCC. The patients were divided into groups according to whether they were taking metformin for the treatment of T2DM, and the expression of EGFR in different groups was compared. Correlation analysis between the expression of EGFR and the fluctuation value of fasting blood glucose (FBG) was carried out. Immunohistochemistry was used to detect the expression of EGFR in cancer tissues of patients with recurrent OSCC. These patients had normal blood glucose and took metformin for a long time after the first operation., Results: EGFR expression in T2DM patients with OSCC taking metformin was significantly lower than that in the non-metformin group. FBG fluctuations were positively correlated with the expression of EGFR in the OSCC tissues of the non-metformin group of T2DM patients. In patients with recurrent OSCC with normal blood glucose, metformin remarkably reduced the expression of EGFR in recurrent OSCC tissues., Conclusion: Metformin may regulate the expression of EGFR in a way that does not rely on lowering blood glucose. These results may provide further evidence for metformin in the treatment of OSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Yang, Shao, Nie, Zhang and Su.)

Objective: To investigate the association between ultrasound appearances and pathological features in small breast cancer., Materials and Methods: A total of 186 small breast cancers in 186 patients were analyzed in this retrospective study from January 2015 to December 2019 according to pathological results. Forty-seven cases of axillary lymph node metastasis were found. All patients underwent radical axillary surgery following conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) examinations. The association between ultrasound appearances and pathological features was analyzed using univariate distributions and multivariate analysis. Then, a logistic regression model was established using the pathological diagnosis of lymph node metastasis and biochemical indicators as the dependent variable and the ultrasound appearances as independent variables., Results: In small breast cancer, risk factors of axillary lymph node metastasis were crab claw-like enhancement on CEUS and abnormal axillary lymph nodes on US. The logistic regression model was established as follows: (axillary lymph node metastasis) = 1.100×(crab claw-like enhancement of CEUS) + 2.749×(abnormal axillary lymph nodes of US) -5.790. In addition, irregular shape on CEUS and posterior echo attenuation on US were risk factors for both positive estrogen receptor and progesterone receptor expression, whereas calcification on US was a risk factor for positive Her-2 expression. A specific relationship could be found using the following logistic models: (positive ER expression) = 1.367×(irregular shape of CEUS) + 1.441×(posterior echo attenuation of US) -5.668; (positive PR expression) = 1.265×(irregular shape of CEUS) + 1.136×(posterior echo attenuation of US) -4.320; (positive Her-2 expression) = 1.658×(calcification of US) -0.896., Conclusion: Logistic models were established to provide significant value for the prediction of pre-operative lymph node metastasis and positive biochemical indicators, which may guide clinical treatment.

Background: Morule-like component (MLC) was a rare structure in primary lung adenocarcinoma. We aimed to reveal the clinicopathological, radiological, immunohistochemical, and molecular features of lung adenocarcinoma with MLCs., Methods: Twenty lung adenocarcinomas with MLCs were collected, and computed tomographic and histological documents were reviewed. Immunohistochemistry, targeted next-generation sequencing, and Sanger sequencing for β-catenin gene were performed., Results: There were 9 lepidic adenocarcinomas, 8 acinar adenocarcinomas, 2 papillary adenocarcinomas, and 1 minimally invasive adenocarcinoma. Most patients (16/17) were shown a pure solid nodule, and 1 patient was shown a partly solid nodule on chest computed tomography (CT). Nine cases were accompanied with micropapillary components, and 3 were with cribriform components in which 2 suffered a worse prognosis. No significant association was found between the MCLs and the overall survival of lung adenocarcinoma ( P = 0.109). The MLCs were often arranged in whorled or streaming patterns. The cells in MLCs showed syncytial and mild appearance. The MLCs were positive for E-cadherin, CK7, TTF-1, napsin-A, vimentin, and β -catenin (membrane), and negative for CK5/6, p40, p63, Synaptophysin, chromogranin A, and Cdx-2. EGFR mutation, ALK-EML4 fusion, HER 2 amplification, and PIK3CA mutation were detected in 16 cases, 2 cases, 1 case, and 1 case, respectively. EGFR mutation was more frequent in adenocarcinomas with MLCs than those without MLCs ( P = 0.040). β-catenin gene mutation was not detected in any patients., Conclusions: MLC is often observed in the background of acinar, lepidic, and papillary adenocarcinomas. Lung adenocarcinomas with MLCs tend to appear as a solid mass on CT and harbor EGFR gene mutations. The micropapillary components and cribriform components may cause poor prognosis of lung adenocarcinomas with MLCs. Vimentin is always positive in MLCs, and it is a useful marker for the identification of MLCs., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Li-Li Wang et al.)

Purpose: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL., Patients and Methods: In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety., Results: The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients., Conclusion: Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations., Competing Interests: Nathan H. FowlerEmployment: BostongeneConsulting or Advisory Role: Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene, NovartisResearch Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, AbbVie, BeiGene Felipe SamaniegoConsulting or Advisory Role: Astex Pharmaceuticals, ADC Therapeutics, Imbrium Therapeutics Wojciech JurczakResearch Funding: TG Therapeutics Nilanjan GhoshConsulting or Advisory Role: Seattle Genetics, TG Therapeutics, AstraZeneca, Verastem, Pharmacyclics/Janssen, Karyopharm Therapeutics, Genmab, Bristol-Myers Squibb, Gilead Sciences, Adaptive Biotechnologies, Beigene, AbbVie, IncyteSpeakers' Bureau: AbbVie, Janssen Oncology, Kite/Gilead Sciences, Seattle Genetics, AstraZeneca, Bristol-Myers Squibb, Celgene, Pharmacyclics/Janssen, EpizymeResearch Funding: Pharmacyclics, TG Therapeutics, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb/Celgene, Gilead Sciences Enrico DerenziniConsulting or Advisory Role: AstraZenecaResearch Funding: TG-Therapeutics, ADC Therapeutics James A. ReevesResearch Funding: Sarah Cannon Research Institute, Eli Lilly, Tesaro, TG Therapeutics, Genentech, Celgene, Merck, Bristol-Myers Squibb, Boston Biomedical Inc, AstraZeneca, NovoCure, Calithera Biosciences, Novartis, Guardant Health, Acerta Pharma, Rhizen Pharmaceuticals, Takeda, Onconova Therapeutics, Sanofi, CTI Biopharma, Eisai, Janssen Chan Y. CheahHonoraria: Roche/Genentech, Janssen-Cilag, TG Therapeutics, Loxo/Lilly, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Ascentage Pharma, MDSConsulting or Advisory Role: Janssen-Cilag, Roche/Genentech, TG Therapeutics, Loxo/Lilly, Gilead Sciences, AstraZeneca, Bristol-Myers Squibb, Ascentage Pharma, MDSSpeakers' Bureau: Janssen-CilagResearch Funding: Roche, Celgene, AbbVieTravel, Accommodations, Expenses: Roche Tycel PhillipsHonoraria: Seattle Genetics, Incyte, Pharmacyclics, Bayer, Gilead Sciences, GenentechConsulting or Advisory Role: Seattle Genetics, Pharmacyclics, Incyte, Genentech, Bayer, Gilead Sciences, Curis, Kite/Gilead, Celgene, GenmabResearch Funding: AbbVie, Pharmacyclics/Janssen, Bayer Ewa Lech-MarandaConsulting or Advisory Role: Roche, Amgen, AbbVie, Astellas Pharma, Novartis, Janssen-Cilag, Sanofi/Aventis, Takeda, Gilead Sciences Bruce D. ChesonConsulting or Advisory Role: TG Therapeutics, AbbVie, Pharmacyclics/Janssen, Morphosys, Celgene, Karyopharm Therapeutics, Epizyme, Gilead Sciences, SymBio Pharmaceuticals, Parexel, Merck, Glaxo Smith Kline, Beigene, Kite, Reddy Biosimilar, Bayer, CelgeneResearch Funding: TG Therapeutics, Trillium Therapeutics, Seattle Genetics, Bristol-Myers Squibb, Gilead Sciences, Pharmacyclics, AbbVie, AstraZenecaTravel, Accommodations, Expenses: SymBio Pharmaceuticals Paolo F. CaimiConsulting or Advisory Role: Genentech, Seattle Genetics, TG Therapeutics, Kite Pharma, ADC Therapeutics, Bayer, Amgen, Verastem, EpizymeSpeakers' Bureau: CelgeneResearch Funding: Genentech, ADC Therapeutics Lori A. LeslieConsulting or Advisory Role: Kite/Gilead, TG Therapeutics, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZenecaSpeakers' Bureau: Kite Pharma, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZeneca, Epizyme, Karyopharm Julio C. ChavezConsulting or Advisory Role: Kite/Gilead, Novartis, Karyopharm Therapeutics, MorphoSys, TeneoBio, AbbVie, JanssenSpeakers' Bureau: AstraZeneca, BeiGene, MorphoSys, EpizymeResearch Funding: Merck Gustavo FonsecaHonoraria: Amgen, CelgeneConsulting or Advisory Role: Amgen, Celgene, Bayer, Abvie/Pharmacyclics, Dava Oncology, KaryopharmSpeakers' Bureau: Amgen, CelgeneResearch Funding: Celgene, Amgen, TG Therapeutics, Verastem OncologyTravel, Accommodations, Expenses: Amgen, Celgene Sunil BabuStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol-Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite Pharma, Janssen OncologySpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol-Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, AbbVie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Daniel J. HodsonResearch Funding: Gilead Sciences John M. BurkeConsulting or Advisory Role: Genentech/Roche, AbbVie, Seattle Genetics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem, MorphoSys, Kura Oncology, Epizyme, BeiGene, Kymera, NovartisSpeakers' Bureau: Seattle Genetics, Beigene Jeff P. SharmanLeadership: US OncologyConsulting or Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, Beigene, PfizerResearch Funding: Pharmacyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda John M. PagelConsulting or Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, BeiGene, Loxo Hari P. MiskinEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Peter SportelliEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Owen A. O'ConnorEmployment: TG TherapeuticsLeadership: TG TherapeuticsBoard Appointments, Stock, and Other Ownership Interests: TG Therapeutics, Kymera, Myeloid Therapeutics, NomoCan PharmaceuticalsHonoraria: MundipharmaConsulting or Advisory Role: Mundipharma Research, Astex PharmaceuticalsResearch Funding: Merck, Celgene/Bristol-Myers Squibb, Seagen, Mundipharma, Astex Pharmaceuticals, ADC Therapeutics Michael S. WeissEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Pier Luigi ZinzaniConsulting or Advisory Role: Sanofi, Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko Kirin, TG Therapeutics, TakedaSpeakers' Bureau: Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko KirinNo other potential conflicts of interest were reported.

The androgen receptor (AR) is expressed in prostate fibroblasts in addition to normal prostate epithelial cells and prostate cancer (PCa) cells. Moreover, AR activation in fibroblasts dramatically influences prostate cancer (PCa) cell behavior. Androgen deprivation leads to deregulation of AR downstream target genes in both fibroblasts and PCa cells. Here, we identified LIM domain only 2 (LMO2) as an AR target gene in prostate fibroblasts using ChIP-seq and revealed that LMO2 can be repressed directly by AR through binding to androgen response elements (AREs), which results in LMO2 overexpression after AR deactivation due to normal prostate fibroblasts to cancer-associated fibroblasts (CAFs) transformation or androgen deprivation therapy. Next, we investigated the mechanisms of LMO2 overexpression in fibroblasts and the role of this event in non-cell-autonomous promotion of PCa cells growth in the androgen-independent manner through paracrine release of IL-11 and FGF-9. Collectively, our data suggest that AR deactivation deregulates LMO2 expression in prostate fibroblasts, which induces castration resistance in PCa cells non-cell-autonomously through IL-11 and FGF-9., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To evaluate the performance of contrast-enhanced ultrasound in the diagnosis of small, solid, TR3-5 benign and malignant thyroid nodules (≤1 cm)., Methods: From January 2016 to March 2018, 185 thyroid nodules from 154 patients who underwent contrast enhanced ultrasound (CEUS) and fine-needle aspiration or thyroidectomy in Shanghai General Hospital were included. The χ 2 test was used to compare the CEUS characteristics of benign and malignant thyroid nodules, and the CEUS features of malignant nodules assigned scores. The total score of the CEUS features and the scores of the above nodules were evaluated according to the latest 2017 version of the Thyroid Imaging Reporting and Data System (TI-RADS). The diagnostic performance of the two were compared based on the receiver operating characteristic curves generated for benign and malignant thyroid nodules., Results: The degree, enhancement patterns, boundary, shape, and homogeneity of enhancement in thyroid small solid nodules were significantly different ( p ＜0.05). No significant differences were seen between benign and malignant thyroid nodules regarding completeness of enhancement and size of enhanced lesions ( p ＞0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the TI-RADS classification TR5 in diagnosis of malignant nodules were 90.10%, 55.95%, 74.59%, 72.22%, and 82.46%, respectively (area under the curve [AUC]=0.738; 95% confidence interval[CI], 0.663-0.813). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the total score of CEUS qualitative analysis indicators were 86.13%, 89.29%, 87.57%, 90.63%, and 84.27% respectively (AUC = 0.916; 95% CI, 0.871-0.961)., Conclusion: CEUS qualitative analysis is superior to TI-RADS in evaluating the diagnostic performance of small, solid thyroid nodules. Qualitative analysis of CEUS has a significantly higher specificity for diagnosis of malignant thyroid nodules than TI-RADS., Advances in Knowledge: The 2017 version of TI-RADS has recently suggested the malignant stratification of thyroid nodules by ultrasound. In this paper we applied this system and CEUS to evaluate 185 nodules and compare the results with pathological findings to access the diagnostic performance.

Aims: Pulmonary peripheral glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) have very similar histological features to pulmonary ciliated muconodular papillary tumour (CMPT)/bronchiolar adenoma (BA). The underlying genetic relationships between GP/MP and CMPT/BA have rarely been characterised. We aimed to reveal the relationship between them., Methods and Results: We performed a clinicopathological review and next-generation sequencing (NGS) study of two GPs and five MPs. Histologically, GPs/MPs showed similar cellular and architectural features to CMPTs/BAs, such as bilayered epithelium, bronchiole-associated lesions and skipping (discontinuous) growth pattern. One MP showed partial and inconspicuous endobronchiolar growth and more glandular structures, which was very similar to the appearance of CMPT/BA. BRAF V600E mutation was detected in four papillomas (57.1%, one GP and three MPs)., Conclusions: Overlapping morphological features and comparable mutation profiles support that peripheral GPs/MPs and CMPTs/BAs are on the same disease spectrum. We propose expanding the concept of CMPT/BA and including GP and MP in the CMPT/BA family., (© 2020 John Wiley & Sons Ltd.)

Background: Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0-1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety., Results: One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95-11.96) for necuparanib arm and 9.99 months (95% CI: 7.85-12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66-1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%)., Conclusion: The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243., Competing Interests: Conflict of interest statement E.M. O.’R. received research funding to MSK: Momenta Pharmaceuticals, Genentech, Roche, BMS, Celgene, MabVax Therapeutics, ActaBiologica, Parker Institute, AstraZeneca, Silenseed. She is a consulting/advisory to Cytomx, BioLineRx, Targovax, Celgene, Bayer, Loxo, Polaris, Merck, AstraZenica to Consulting/advisory. D.M. received research funding from Oncolytics and Merck and is a consultant/advisory to Amgen, Bayer, BMS, Eisai, EMD Serono, Exelexis, Genentech. T.B.S. is a consultant to Imugene, Immuneering, Bayer, Genentech, Incyte, Ipsen, Exelexis, Lilly, Astra-Zeneca, Merck and Array. M.R., J.M.R.: Momenta Pharmaceuticals (former employee). K.T.F. is Board of Directors at Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals; he is also in Corporate Advisory Board of X4 Pharmaceuticals, PIC Therapeutics, Scientific Advisory Board of Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, and he is Consultant for Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm. D.R.: Equity: MPM Capital, Acworth Pharmaceuticals, is on Advisory Board of MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics. Publishing: Johns Hopkins University Press, Uptodate McGraw Hill. All other authors have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To identify the efficacy of contrast-enhanced ultrasound (CEUS) in re-evaluating masses with inconsistent Breast Imaging Reporting and Data System (BI-RADS) on mammography (MG) and conventional ultrasound (US)., Materials and Methods: A total of 637 breast lesions were evaluated with MG, US, and CEUS within 6 months and assessed as BI-RADS MG and US. CEUS was used as an additional screening to rerate BI-RADS US according to a five-point system. Lesions were divided into consistent or inconsistent group on the basis of BI-RADS MG and US assessment. The performance of MG, US, and CEUS in the overall and inconsistent group as well as the clinicopathological differences between consistent and inconsistent group were compared using Z test, Mann-Whitney U test, and t-test., Results: The respective AUCs of MG and US were 0.742, 0.843 for overall group and 0.412, 0.789 for inconsistent group. The corresponding values of rerated CEUS BI-RADS were 0.958 and 0.950, which were significantly prior to those of MG and US (p < 0.001). Younger age, negative lymph node status, and dense breast were significantly associated with inconsistent group., Conclusion: Incorporation of CEUS to re-evaluate lesions can improve the diagnostic efficacy comparing to MG or US alone especially when disagreement occurred.

Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.

The activation of androgen receptor (AR) signaling plays an essential role in both prostate stromal cells and epithelial cells during the development of benign prostatic hyperplasia (BPH). Here we demonstrated that androgen ablation after 5α-reductase inhibitor (5-ARI) treatment induced autophagy in prostate stromal fibroblasts inhibiting cell apoptosis. In addition, we found that ATG9A expression was increased after androgen ablation, which facilitated autophagic flux development. Knockdown of ATG9A not only inhibited autophagy notably in prostate stromal fibroblasts, but also reduced the volumes of prostate stromal fibroblast and epithelial cell recombinant grafts in nude mice. In conclusion, our findings suggested that ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Thus, combined treatment with 5-ARI and autophagy inhibitory agents would reduce the risk of BPH progression.

The inadequate supply of transplantable organs necessitates new approaches to organ availability. Serologies and nucleic acid testing (NAT) for hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are used in microbiologic screening of potential organ donors. Organs from donors considered at "high risk" (Centers for Disease Control and Prevention, CDC 1994) or "increased risk" (U.S. Public Health Service, PHS 2013) for transmission of viral infection to recipients may provide an expanded source of organs for transplantation. We review a single-center experience with 257 adult organ recipients of organs from donors meeting either CDC 1994 or PHS 2013 risk criteria between 2011 and 2016. Tracking these transplants required modification of the Transplant Center electronic database to identify all recipients of increased-risk donor (IRD) organs, documentation of informed consent, and microbiologic testing data. No transmissions of HIV, HBV, or HCV were identified by NAT or clinically. Nine patients developed positive serologic assays for one of the tested viruses; all recipients were retested and remain negative by NAT. Notably, post-transplant HBV core serologies reverted to negative on re-testing; these positive serologies are likely false positives caused by receipt of blood products. Use of IRD organs can be performed safely with appropriate informed consent and rigorous pre- and post-transplant microbiological testing., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Irradiation with 6 Gy produces a complete block of spermatogonial differentiation in LBNF1 rats that would be permanent without treatment. Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6 weeks. We evaluated the role of Leydig cells (LCs) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional LCs with ethane dimethane sulfonate (EDS). EDS (but not another alkylating agent), given at 10 weeks after irradiation, induced spermatogonial differentiation in 24% of seminiferous tubules 2 weeks later. However, differentiation became blocked again at 4 weeks as LCs recovered. When EDS was followed by treatment with GnRH antagonist and flutamide, sustained spermatogonial differentiation was induced in >70% of tubules within 2 weeks. When EDS was followed by GnRH antagonist plus exogenous T, which also inhibits LC recovery but restores follicle stimulating hormone (FSH) levels, the spermatogonial differentiation was again rapid but transient. These results confirm that the factors that block spermatogonial differentiation are indirectly regulated by T, and probably FSH, and that adult and possibly immature LCs contribute to the production of such inhibitory factors. We tested whether insulin-like 3 (INSL3), a LC-produced protein whose expression correlated with the block in spermatogonial differentiation, was indeed responsible for the block by injecting synthetic INSL3 into the testes and knocking down its expression in vivo with siRNA. Neither treatment had any effect on spermatogonial differentiation. The Leydig cell products that contribute to the inhibition of spermatogonial differentiation in irradiated rats remain to be elucidated., (© 2016 American Society of Andrology and European Academy of Andrology.)

The duodenal ulcer promoting gene (dupA), located in the plasticity region of Helicobacter pylori (H. pylori), is predicted to form a type IV secretory system (T4SS) with vir genes around dupA. In the study, we investigated the association between the dupA cluster status and the virulence of H. pylori in a littoral region of Northeast China. Two hundred and sixty-two H. pylori strains isolated from the chronic gastritis were examined to evaluate the dupA cluster status, cag PAI genes and vacA genotype using PCR and Western blot. Histopathologic evaluations of biopsy specimens were performed to analysis the association between the dupA cluster and the inflammatory response. IL-8 productions in gastric mucosa and from GES-1 cells co-cultured with H. pylori were measured, respectively, to analysis the association between the dupA cluster status and IL-8 production. We found that gastric mucosal inflammatory cell infiltration was significantly higher in patients with dupA-positive H. pylori, including H. pylori with complete dupA cluster (2.71 ± 0.79) and incomplete dupA cluster (2.09 ± 0.61) than in patients with dupA-negative strain (1.73 ± 0.60, p < 0.01), whereas no significant difference in the gastric mucosal atrophy was found according to the status of dupA cluster. Gastric mucosal IL-8 levels were higher in the complete dupA cluster group than in other groups (p < 0.01), and IL-8 production from GES-1 cells was also significantly higher in strains with a complete dupA cluster (1527.9 ± 180.0 pg/ml) than in those with an incomplete dupA cluster (1229.4 ± 75.3 pg/ml, p < 0.01) or those with dupA negative (1201.9 ± 92.3 pg/ml, p < 0.01). In conclusion, the complete dupA cluster in H. pylori is associated with inflammatory cell infiltration and IL-8 secretion, and H. pylori strain with a complete dupA cluster seems to be more virulent than other strains with the incomplete dupA cluster or dupA negative.

The function of intact long-type DupA protein in Helicobacter pylori was analyzed using immunoblotting and molecular biology techniques in the study. After cloning, expression and purification, ATPase activity of DupA protein was detected. Antibody was produced for localization and interaction proteins analysis. The dupA-deleted mutant was generated for adhesion and CagA protein translocation assay, susceptibility to different pH, IL-8 secretion assay, cytotoxicity to MKN-45 cells and proteins-involved apoptosis analysis. DupA protein exhibited an ATPase activity (129.5±17.8 U/mgprot) and located in bacterial membrane, while it did not involve the adhesion and CagA protein delivery of H. pylori. DupA protein involved the urease secretion as the interaction proteins. The wild type strain had a stronger growth in low pH than the dupA-deleted mutant (p < 0.001). IL-8 productions from GES-1 cells infected with the wild type strain were significantly higher than from those with the mutant (p < 0.001). The amounts of vital MKN-45 cells were decreased and the numbers of apoptotic cells were increased with the wild type strain, compared to those with the mutant after 12 h (p < 0.05). The increase of cleaved Caspase-3 and Bax was significantly higher and the decrease of Bcl-2 was more obvious in MKN-45 cells exposed to the wild type strain than that exposed to the mutant after 6 h. We demonstrate that intact long-type DupA protein located in membrane as ATPase is a true virulence factor associated with duodenal ulcer development involving the IL-8 induction and urease secretion, while it inhibits gastric cancer cell growth in vitro by activating the mitochondria-mediated apoptotic pathway., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To investigate the expression of CP in Down syndrome (DS) mouse model, we especially observed the changes in neuronal CP. We systematically analyzed the level of CP in Ts65Dn mouse, including serum CP concentration and enzymatic activity, CP mRNA in brain, the expression of CP protein in brain. The applied technologies were ELISA, chemical colorimetry, RT-PCR, immunohistochemistry. Compared with the control group, there were no differences of significance in the concentration, enzymatic activity and unit activity of serum ceruloplasmin. By RT-PCR, we also found there were no significant differences in the level of CP mRNA. The expression of CP was positive in the endochylema of neuronal cells of both the groups, and there were no significant difference between the two groups. Meanwhile, there were no differences in four regions of the brain (cerebral cortex, hippocampus, thalamus and cerebella). Although the neurotoxic effects of CP related to some neurodegenerative diseases, but whether it does so in DS remains to be determined.

Background: Primary mucinous cystadenocarcinoma of the breast is an extremely rare entity. To the best of our knowledge, only 17 patients have been described in the PubMed database., Case Report: Here, we report a primary breast mucinous cystadenocarcinoma with endocervical-like mucinous epithelium in a 62-year-old woman. The patient was followed for 5 months without any adjuvant treatment and she continues to be disease free., Conclusions: Primary breast mucinous cystadenocarcinoma usually displays unique pathologic and immunohistochemical characteristics simulating its ovarian counterparts; it seems to have a good prognosis after complete resection.

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

Hormone suppression given before or after cytotoxic treatment stimulates the recovery of spermatogenesis from endogenous and transplanted spermatogonial stem cells (SSC) and restores fertility in rodents. To test whether the combination of hormone suppression and transplantation could enhance the recovery of spermatogenesis in primates, we irradiated (7 Gy) the testes of 12 adult cynomolgus monkeys and treated six of them with gonadotropin-releasing hormone antagonist (GnRH-ant) for 8 weeks. At the end of this treatment, we transfected cryopreserved testicular cells with green fluorescent protein-lentivirus and autologously transplanted them back into one of the testes. The only significant effect of GnRH-ant treatment on endogenous spermatogenesis was an increase in the percentage of tubules containing differentiated germ cells (tubule differentiation index; TDI) in the sham-transplanted testes of GnRH-ant-treated monkeys compared with radiation-only monkeys at 24 weeks after irradiation. Although transplantation alone after irradiation did not significantly increase the TDI, detection of lentiviral DNA in the spermatozoa of one radiation-only monkey indicated that some transplanted cells colonized the testis. However, the combination of transplantation and GnRH-ant clearly stimulated spermatogenic recovery as evidenced by several observations in the GnRH-ant-treated monkeys receiving transplantation: (i) significant increases (~20%) in the volume and weight of the testes compared with the contralateral sham-transplanted testes and/or to the transplanted testes of the radiation-only monkeys; (ii) increases in TDI compared to the transplanted testes of radiation-only monkeys at 24 weeks (9.6% vs. 2.9%; p = 0.05) and 44 weeks (16.5% vs. 6.1%, p = 0.055); (iii) detection of lentiviral sequences in the spermatozoa or testes of five of the GnRH-ant-treated monkeys and (iv) significantly higher sperm counts than in the radiation-only monkeys. Thus hormone suppression enhances spermatogenic recovery from transplanted SSC in primates and may be a useful tool in conjunction with spermatogonial transplantation to restore fertility in men after cancer treatment., (© 2013 American Society of Andrology and European Academy of Andrology.)

Abstract Background: Helicobacter pylori (H. pylori) is a major human pathogen that is responsible for various gastroduodenal diseases. We investigated the prevalence of H. pylori virulence markers in a region at high risk of gastric cancer., Methods: One hundred and sixteen H. pylori strains were isolated from patients with gastroduodenal diseases. cagA, the cagA 3' variable region, cagPAI genes, vacA, and dupA genotypes were determined by PCR, and some amplicons of the cagA 3' variable region, cagPAI genes and dupA were sequenced., Results: cagA was detected in all strains. The cagA 3' variable region of 85 strains (73.3%) was amplified, and the sequences of 24 strains were obtained including 22 strains possessing the East Asian-type. The partial cagPAI presented at a higher frequency in chronic gastritis (44.4%) than that of the severe clinical outcomes (9.7%, p < 0.001). The most prevalent vacA genotypes were s1a/m2 (48.3%) and s1c/m2 (13.8%). Thirty-six strains (31.0%) possessed dupA and sequencing of dupA revealed an ORF of 2449-bp. The prevalence of dupA was significantly higher in strains from patients with the severe clinical outcomes (40.3%) than that from chronic gastritis (20.4%, p = 0.02)., Conclusion: The high rate of East Asian-type cagA, intact cagPAI, virulent vacA genotypes, and the intact long-type dupA may underlie the high risk of gastric cancer in the region., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin)., Patients and Methods: Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status., Treatment: PLD 30 mg/m(2) followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab., Results: Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3-4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%., Conclusions: PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity.

Rapid and accurate detection of Streptococcus pneumoniae (Sp), Haemophilus influenzae type b (Hib) and Mycobacterium tuberculosis complex (MTBC) in sputum by conventional methods remains problematic. Primers based on capsular polysaccharide biosynthesis gene (cpsA), the region II of the capsulation locus (cap), the insertion sequence IS6110 were designed for Sp, Hib, MTBC respectively. These primers were incorporated in a multiplex touchdown PCR assay for simultaneous detection of Sp, Hib and MTBC. The multiplex touchdown PCR assay was evaluated using standard strains and clinical sputum samples. The multiplex touchdown PCR assay showed 100% specificity in identifying Sp, Hib, MTBC from pure culture of standard strains. The sensitivities of the multiplex touchdown PCR assay were 94%, 98%, 98% for detection of Sp, Hib and MTBC respectively based on culture results while evaluated using 492 consecutive qualified clinical sputum samples; the specificities were all 100%. This highly sensitive and specific multiplex touchdown PCR assay offers a rapid and simple method for detection of Sp, Hib and MTBC in clinical sputum samples.

Background: Invasive aspergillosis (IA) is an important cause of mortality in critically ill patients, but the diagnosis is difficult as clinical and radiological signs are neither sensitive nor specific. Serum galactomannan (GM) is a useful marker for IA, but exhibits low sensitivity in non-neutropenic patients. In our previous work, strong antibody reactivity to thioredoxin reductase of Aspergillus fumigatus was found in non-neutropenic IA patients., Methods and Results: Using recombinant thioredoxin reductase GliT (TR), an antigenic protein secreted by A. fumigatus, as the coating antigen, an enzyme-linked immunosorbent assay (ELISA) for detecting anti-TR antibodies was developed. The antibody response to TR in IA animal models and 42 non-neutropenic patients with culture- and/or histology-documented IA was investigated. The results showed that anti-TR antibody was detectable in rabbit serum 7-9 days after exposure to the fungus. The sensitivity and specificity of the anti-TR antibody assay in patients were 80.9% and 96%, respectively, while the sensitivity of GM in this group of patients was only 52.3%. The specificity of the assay was confirmed by testing the sera from patients infected with other pathogenic fungal species and bacteria., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Characterization of novel proteins in maternal serum derived from mothers carrying Down syndrome (DS) fetuses., Material and Methods: Based on last comparative proteomic analysis, five significant differences of expressed proteins in serum from four groups have been confirmed by ELISA. DAVID and GeneGo MetaCore were used to bioinformatically analyze candidate protein markers., Results: The serum levels of ceruloplasmin (CP) and complement factor B (CFB) were significantly increased in mother carried DS fetuses (346.5 ng/ml and 466.8 ng/ml vs. 248.6 ng/ml and 293.5 ng/ml, p< 0.05). Twenty-nine proteins were mainly categorized into binding, catalytic activity and enzyme regulator activity proteins, and their biological roles were involved in biological regulation, metabolic processes, cellular processes, and response to stimuli. The immune response alternative complement pathway was the most significant GeneGo Pathway related to DS., Conclusions: These 29 proteins have relations with the development of Down syndrome, especially CP and CFB play more important roles.

Prenatal screening for Down's syndrome (DS) is in need of improvement. As a powerful platform, proteomics techniques could also be used for identification of new biomarkers for DS screening. In this case-control proteome study, pregnant women were diagnosed prenatally by karyotype analysis from amniotic fluid (AF). Maternal serum samples were collected from six pregnancies with fetuses affected by DS and six pregnancies with normal fetuses. First, we used two-dimensional electrophoresis and mass spectrometry to identify the different levels of expression of proteins in maternal serum between the DS and control groups in the second trimester. Second, we used bioinformatics to analyze the proteins by DAVID. Then, the interesting candidates were further tested by enzyme-linked immunosorbent assay (ELISA). Twenty-nine proteins were successfully identified in maternal serum obtained from pregnancies with fetuses affected by DS. The top five proteins up-regulated were serotransferrin (TF), alpha-1b-glycoprotein (A1BG), desmin (DES), alpha-1-antitrypsin (SERPINA1) and ceruloplasmin (CP), while serum amyloid P-component (APCS) was the most down-regulated protein. These 29 proteins were categorized based on binding, catalytic activity and enzyme regulator activity. The biological roles were involved in biological regulation, metabolic processes, cellular processes and response to a stimulus. Based on ELISA, the median concentrations of CP and complement factor B (CFB) were 332.3 and 412.3 ng/mL, respectively. The concentrations of CP and CFB were significantly higher in the DS group than in the control group (P < 0.05). In conclusion, proteomic approaches offer the possibility of further improving the performance of DS screening and our identification of up- and down-regulated proteins may lead to new candidates for DS screening.

Aims: To investigate the antibiofilm effect of cinnamaldehyde on methicillin-resistant Staphylococcus aureus (MRSA) and analyse the effect of subminimum inhibitory concentrations (MICs) of cinnamaldehyde on the expression of the biofilm-related gene sarA., Methods and Results: The MICs and minimum bactericidal concentrations (MBCs) were determined using a microtitre broth dilution method. Biofilm susceptibility was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining and colony forming unit (CFU) counting assays. Antibiofilm effects were studied with scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). SarA expression was assessed by real-time PCR. MICs and MBCs were in the range 0.0625-0.5% (v/v). The killing effects were concentration dependent. At a concentration of 5× MIC, all strains in biofilm were decreased to lower than 20% of the control groups. SEM and CLSM images indicated that a 5× MIC concentration of cinnamaldehyde was able to detach and kill existing biofilms. Apart from strain JB-06, real-time PCR showed that the expression of sarA of all other strains was decreased upon exposure to sub-MICs of cinnamaldehyde., Conclusions: These data showed the strong killing effect of cinnamaldehyde against MRSA within biofilms., Significance and Impact of the Study: This study indicated the potential of cinnamaldehyde as an inhibitory agent for use in MRSA biofilm-related infections., (© 2011 The Authors. Letters in Applied Microbiology © 2011 The Society for Applied Microbiology.)

Despite numerous observations of the effects of estrogens on spermatogenesis, identification of estrogen-regulated genes in the testis is limited. Using rats in which irradiation had completely blocked spermatogonial differentiation, we previously showed that testosterone suppression with gonadotropin-releasing hormone-antagonist acyline and the antiandrogen flutamide stimulated spermatogenic recovery and that addition of estradiol (E2) to this regimen accelerated this recovery. We report here the global changes in testicular cell gene expression induced by the E2 treatment. By minimizing the changes in other hormones and using concurrent data on regulation of the genes by these hormones, we were able to dissect the effects of estrogen on gene expression, independent of gonadotropin or testosterone changes. Expression of 20 genes, largely in somatic cells, was up- or downregulated between 2- and 5-fold by E2. The unexpected and striking enrichment of transcripts not corresponding to known genes among the E2-downregulated probes suggested that these might represent noncoding mRNAs; indeed, we have identified several as miRNAs and their potential target genes in this system. We propose that genes for which expression levels are altered in one direction by irradiation and in the opposite direction by both testosterone suppression and E2 treatment are candidates for controlling the block in differentiation. Several genes, including insulin-like 3 (Insl3), satisfied those criteria. If they are indeed involved in the inhibition of spermatogonial differentiation, they may be candidate targets for treatments to enhance recovery of spermatogenesis following gonadotoxic exposures, such as those resulting from cancer therapy.

Why both testosterone (T) suppression and cryptorchidism reverse the block in spermatogonial differentiation in adult mice homozygous for the juvenile spermatogonial depletion (jsd) mutation has been a conundrum. To resolve this conundrum, we analyzed interrelations between T suppression, testicular temperature, and spermatogonial differentiation and used in vitro techniques to separate the effects of the two treatments on the spermatogonial differentiation block in jsd mice. Temporal analysis revealed that surgical cryptorchidism rapidly stimulated spermatogonial differentiation whereas androgen ablation treatment produced a delayed and gradual differentiation. The androgen suppression caused scrotal shrinkage, significantly increasing the intrascrotal temperature. When serum T or intratesticular T (ITT) levels were modulated separately in GnRH antagonist-treated mice by exogenous delivery of T or LH, respectively, the inhibition of spermatogonial differentiation correlated with the serum T and not with ITT levels. Thus, the block must be caused by peripheral androgen action. When testicular explants from jsd mice were cultured in vitro at 32.5 C, spermatogonial differentiation was not observed, but at 37 C significant differentiation was evident. In contrast, addition of T to the culture medium did not block the stimulation of spermatogonial differentiation at 37 C, and androgen ablation with aminoglutethimide and hydroxyflutamide did not stimulate differentiation at 32.5 C, suggesting that T had no direct effect on spermatogonial differentiation in jsd mice. These data show that elevation of temperature directly overcomes the spermatogonial differentiation block in adult jsd mice and that T suppression acts indirectly in vivo by causing scrotal regression and thereby elevating the testicular temperature.

Brain-derived neurotrophins factor (BDNF) belongs to the neurotrophins family which acts on neuronal survival and growth and has been associated with cognition process. TrkB is the primary signal transduction receptor for BDNF. In the present study, hippocampal BDNF and TrkB mRNA were detected by RT-PCR in 2- and 22-month rats, respectively, which were exposed to different durations of mild stress protocol of 8-day, 21-day and 28-day chronic unpredictable mild stress (CUMS). Observation of exploratory behavior in an open field (OF) test indicated stress levels and changes of spontaneous activity. We demonstrated that CUMS induced decrease of BDNF mRNA in two aged groups, but the increase change of TrkB mRNA compared with those of the control groups. Moreover, the changes of BDNF mRNA and TrkB mRNA measured in both the 21-day and 28-day stress groups represent obvious decrease than those of the 8-day stress groups, and the expression examined in young groups appeared to be higher than those of the aged group, especially in the 28-day stress groups. Results of OF test showed that explicit behaviors in two age groups decreased gradually with the process of stress revealing a depressive state under the stress condition. Meanwhile, the behaviors of young rats seemed to be more active than those of the aged rats, exhibiting weak adaptation to the stress. The study suggested that stress paradigm and aging certainly had effect on the regulation of BDNF mRNA and TrkB mRNA which might be related to damage and protection function of the hippocampus.

Objective: To investigate the mechanism of norcantharidin (NCTD)-induced SMMC-7721 hepatoma cell apoptosis., Methods: SMMC-7721 cell growth inhibition was measured by the MTT method. Apoptosis was detected by Annexin V/propidium iodide staining. The mitochondrial membrane potential was measured by flow cytometry. Western blot analysis was used to evaluate the level of cytochrome c, caspase-3, AIF, Bcl-2 and Bax expression., Results: NCTD inhibited SMMC-7721 cell growth in a time- and dose-dependent manner. The cells treated with NCTD showed the loss of mitochondrial membrane potential. The activities of caspase-3, cytochrome c, AIF, and Bax were up-regulated after NCTD treatment at different doses. The expression of Bcl-2 was decreased after treatment with NCTD., Conclusions: NCTD could induce SMMC-7721 cell apoptosis. The activation of the mitochondrial pathway was involved in the process of NCTD-induced SMMC-7721 cell apoptosis.