Acquired tamoxifen resistance is surmounted by GW8510 through ribonucleotide reductase M2 downregulation-mediated autophagy induction.

Tamoxifen resistance is a major roadblock in the treatment of patients with breast cancer. Ribonucleotide reductase M2 (RRM2) was found to be involved in acquired resistance of breast cancer cells (BCCs) to tamoxifen. Here, we used GW8510, which has been identified as a potential RRM2 inhibitor, to evaluate the effect of RRM2 inhibition on reversing resistance of BCCs to tamoxifen and investigate its mechanisms. We showed that RRM2 overexpression played a key role in the development of acquired tamoxifen resistance in BCCs through downregulation of autophagy level. Combination treatment with tamoxifen and GW8510 significantly inhibited survival of the tamoxifen-resistant BCCs through induction of autophagic cell death compared to either of the two drugs. Furthermore, combination of tamoxifen and GW8510 resulted in marked growth inhibition of tamoxifen-resistant BBC xenograft tumor in vivo compared to tamoxifen or GW8510 alone. In conclusion, tamoxifen in combination with GW8510 can overcome acquired tamoxifen resistance in BCCs and may be a rational therapeutic approach against breast cancer with high RRM2 expression.

Nitric oxide blocks the development of the human parasite Schistosoma japonicum.

Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS-/-) Sprague-Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS-/- rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host-parasite interactions and drug development strategies against schistosomiasis.

Risk factors and survival analysis of haemodialysis complicated with infective endocarditis.

The clinical features and risk factors for survival time were analysed in haemodialysis patients complicated with infective endocarditis. A total of 101 infective endocarditis (IE) patients treated at Hangzhou First People's Hospital, from January 1, 2012, to April 1, 2022, were included in the present study. Baseline demographic data and laboratory data were collected for statistical analysis of risk factors and survival time in the IE with haemodialysis group (HD-IE group, n=15) and the IE without haemodialysis group (NHD-IE group, n=86). Haemoglobin, red blood cells, C-reactive protein, procalcitonin, serum albumin, diabetes, invasive procedures, positive blood bacteria culture, heart valve calcification ratio, and left ventricular ejection fraction level were risk factors for infective endocarditis complicated with haemodialysis (P<0.05). Compared with the NHD-IE group, the HD-IE group had an obviously increased risk of mortality (χ2=6.323, P=0.012). The univariate Cox regression analysis showed that age, haemoglobin, red blood cells, serum albumin, left ventricular ejection score, longest vegetation diameter, combined hypotension and diabetes were risk factors for death; furthermore, multivariate Cox regression showed that age (HR=1.187, P=0.015), combined hypotension (HR=0.921, P=0.025) and the longest vegetation diameter (HR=9.191, P=0.004) were independent risk factors affecting the survival of patients. Collectively, the present study revealed that the mortality rate of HD-IE patients was higher than that of NHD-IE patients. Older age, hypotension, and the longest vegetation diameter were independent risk factors affecting the survival of patients. For HD-IE patients, active and effective antibiotic treatment or surgical treatment should be strongly recommended.

Clinical and radiologic features of the first cured Coronavirus disease 2019 (COVID-19) patient in Guangzhou City, China.

To determine changes in clinical and radiologic findings associated with Coronavirus disease 2019 (COVID-19) from diagnosis to recovery, we retrospectively reviewed the diagnosis and treatment records of the first patient cured of COVID-19 in Guangzhou. A 55-year-old woman from Wuhan was admitted to the hospital isolation ward with the chief complaint of "cough for 11 days and once fever 8 days ago" on January 22, 2020. COVID-19 was laboratory confirmed by reverse transcription polymerase chain reaction (RT-PCR) assay, and she received conventional antiviral therapy, such as moxifloxacin, traditional Chinese medicine, and arbidol. Repeat chest-computed tomography (CT) scans were performed on days 13 and 19 of her illness. The former showed radiologic findings, including ground-glass opacities (GGOs), which revealed viral pneumonia; the latter revealed that the previous lesions had been significantly absorbed. The lesions on CT scans were consistent with the changes in the course of disease. Some drugs, such as traditional Chinese medicine and arbidol, might play an important role in the recovery of COVID-19 patients. This study provides some new insights into the formulation of a timely and effective diagnostic and therapeutic strategy to cure patients with COVID-19.

Discrimination of Various Amine Vapors by a Triemissive Metal-Organic Framework Composite via the Combination of a Three-Dimensional Ratiometric Approach and a Confinement-Induced Enhancement Effect.

Multiemissive sensors are being actively pursued, because of their ratiometric luminescent detection capabilities, which demonstrates better sensitivity and selectivity than conventional single-emission sensors. Herein, we present a trichromatic white-light-emitting metal-organic framework (MOF) composite (Z3) by simultaneously incorporating red/green-emitting Pt/Ru complex cations into porous blue-emitting bio-MOF-1 through post-synthetic modification. With the help of a three-dimensional (3-D) dual-ratiometric luminescence recognition method, and unique turn-on responses of the red emission toward amine compounds (ACs), including NH3 and aliphatic amines, via confinement-induced luminescence enhancement effect, Z3 can work as a dual-ratiometric luminescent sensor for discrimination of 7 out of 11 AC vapors. This work not only provides a new AC sensing mechanism (confinement effect) that can induce a "turn-on" response but also proves that the accuracy and selectivity of composite sensor can be greatly improved through the combination of 3-D recognition method and the confinement effect. Thus, it open up fresh opportunities to develop composite sensors with excellent sensing and differentiating ability.

Bisdemethoxycurcumin Enhances the Sensitivity of Non-small Cell Lung Cancer Cells to Icotinib via Dual Induction of Autophagy and Apoptosis.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.

[Apoptosis and activity changes of telomerase induced by essential oil from pine needles in HepG2 cell line].

OBJECTIVE: To study the effects of essential oil extracted from pine needles on HepG2 cell line. METHODS: HepG2 cells were treated with essential oil extracted from pine needles. Cell growth rate was determined with MTF assay, cell morphologic changes were examined under transmission electromicroscope and HE straining. Flow cytometry was used to exmine apoptotic cells. Bcl-2 gene expression was determined by flow cytometry and telomerase activity by TRAP assay. RESULTS: Essential oils from pine needles could not only repress the growth of HepG2 cells significantly, but also induce apoptosis to them. Both dose-effect and time-effect relationship could be confirmed. Typical morphology changes of apoptosis such as nuclear enrichment and karyorrhexis were observed through transmission electromicroscope and HE straining. Telomerase activity was down regulated in the essential oil extracted from pine needles induced apoptotic cells. The expression of bcl-2 gene was suppressed after the essential oil from pine needles treatement. CONCLUSION: The essential oil extracted from pine needles can inhibit cell growth of HepG2 cell line and induce apoptosis, which may associate with inhibition of telomerase activity and bcl-2 may be involved in the regulation of telomerase activity.

Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine.

The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC.

Co-inhibition of pol θ and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival.

Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer. However, the main obstacle of the efficacy of treatment is drug resistance. Here, we show that expression of translesion synthesis (TLS) polymerase Q (POLQ) was significantly elevated by exposure of lung cancer cells A549/DR (a cisplatin-resistant A549 cell line) to cisplatin. POLQ expression correlated inversely with homologous recombination (HR) activity. Co-depletion of BRCA2 and POLQ by siRNA markedly increased sensitivity of A549/DR cells to cisplatin, which was accompanied with impairment of double strand breaks (DSBs) repair reflected by prominent cell cycle checkpoint response, increased chromosomal aberrations and persistent colocalization of p-ATM and 53BP1 foci induced by cisplatin. Thus, co-knockdown of POLQ and HR can efficiently synergize with cisplatin to inhibit A549/DR cell survival by inhibiting DNA DSBs repair. Similar results were observed in A549/DR cells co-depleted of BRCA2 and POLQ following BMN673 (a PARP inhibitor) treatment. Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1. Our results indicate that there is a synthetic lethal relationship between pol θ-mediated DNA repair and HR pathways. Pol θ may be considered as a novel target for lung cancer therapy.

[Relationship between polymorphism of growth hormone gene and production traits in goats].

Growth hormone (GH) plays an important role in animal growth and development, and the growth hormone gene can be considered as a candidate gene for studying the weight in goats. The function of GH gene has been intensively studied in cattle and pigs, while in goats the study is still rare. In this paper 224 goats including LuBei White goat, Boer goat, hybrid generation 1 and backcross generation 1 of Boer goat and LuBei White goat were used. Two pairs of primers for 5' region of GH gene were designed according to the database of goat genomic sequence (Accession No. D00476) and polymorphisms were detected by PCR-SSCP. Homozygotes of the polymorphic fragment were cloned and sequenced. The result showed that there were five substitution mutations in the two fragments. Statistical analysis showed that in the fragment amplified by the first pair of primers, AA genotype had significant higher birth weight and weight of one year old than BB and AB genotypes in Boer goats (P<0.05). In hybrid generation 1 AA genotype also had higher birth weight and weight of one year old in significantly. While in LuBei White goats BB genotype had lower weight and the weaning weight was significant lower than the other two genotypes (P<0.05). In the fragment amplified by the second pair of primers there was no significant difference among different genotypes. From these results we can preliminarily draw the conclusion that GH gene may be a major gene or linked to the major gene to affect the weight traits and the polymorphic site could be used to select the goat weight in marker-assisted selection program.

[The long-term effect of phacoemulsification combined with trabeculectomy and intraoperative 5-fluorouracil in glaucoma patients].

OBJECTIVE: This study was designed to evaluate the long-term effect of phacoemulsification, lens implantation combined with trabeculectomy augmented with 5-Fluorouracil (phaco-trab-5-Fu) in Asian glaucoma patients with primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). METHODS: This retrospective study included 71 consecutive patients who underwent phaco-trab-5-Fu in Singapore National Eye Center between January 1996 and December 1998. Patients with follow-up time less than 6 months were excluded from the study. RESULTS: The mean follow-up time was (53.1 +/- 20.9) months. Postoperative IOP was significantly lower than preoperation [(15.0 +/- 4.0) mmHg (1 mmHg = 0.133 kPa), (20.3 +/- 5.4) mmHg, respectively, P < 0.01]. Postoperative number of antiglaucoma medications was also significantly decreased than preoperation (P < 0.01). IOP of 1 to 5 years postoperation dropped significantly from that of preoperation (P < 0.01). Complete success (CS) rate of phaco-trab-5-Fu was 84.2%, 62.7%, 55.3% for 1, 3, 5 years, respectively. There were neither significant difference found in PACG group and POAG group, or in single-incision and separate-incision of CS rate. But mean IOP of last follow-up was significantly different between PACG and POAG [mean IOP (13.8 +/- 4.6) mmHg, (16.2 +/- 3.7) mmHg, respectively, P = 0.02]. According to LogMAR chart, mean preoperative visual acuity (VA) and postoperative VA were 0.75 +/- 0.40 and 0.46 +/- 0.46, respectively. Postoperative VA was significantly improved (P < 0.01). In visual field, MD were (-16.6 +/- 8.8) dB and (-17.6 +/- 10.1) dB at preoperation and postoperation, respectively. PSD were (6.2 +/- 2.9) dB and (6.5 +/- 3.2) dB correspondingly. There were no significant difference in both MD and PSD (P = 0.55, 0.64, respectively). One patient had early endophthalmitis and required vitrectomy. Two late-onset of hypotony were due to choroidal effusion and wound leak. CONCLUSIONS: Phacoemulsification combined with trabeculectomy and 5-Fu could be a successful and safe treatment for patients with cataract and primary glaucoma in a long run. There is no difference in success rate in PACG and POAG, or in single incision or separate incision in such combined surgery.

[Polymorphism analysis of the goat growth hormone gene in the 5' regulatory sequence].

The polymorphism of goat growth hormone gene in 5'-region in 274 goats including Lubei white goat, introducted Boer goat, pure bred Boer goat , hybrid generation 1 of LuBei white goat and Boer goat , backcross of hybrid generation 1 and Boer goat were detected by PCR-SSCP with two different pairs of primers. The result showed that in 26-239bp most of the Boer goats and hybrid generation presented as AA genotype,while most LuBei white goats presented as BB genotype. In 225-429bp all breeds presented as more CC genotype. The amplified fragments of AA,BB and CC,DD of the two fragments were cloned and sequenced . The result showed that in 26-239bp AA genotype had one substitution mutation at 60 site (C-->T), and base C losing at 211 site and DD genotype had three substitution mutations at 264 site (T-->C), 292 site (T-->A) and 372 site (C-->T) in 225-429bp. The results above-mentioned first confirmed that there were polymorphisms in 5' region of GH gene.

[Long-term effect of trabeculotomy on primary congenital glaucoma].

OBJECTIVE: To evaluate the long-term effect of trabeculotomy on primary congenital glaucoma. METHODS: This retrospective study included primary congenital glaucoma patients who underwent trabeculotomy as an initial surgery between 1988 and 1999 with follow-up at least one year. Definitions of successful operation were determined as (1) intraocular pressure (IOP) /= 0.4, 29.1% between 0.1 and 0.3, and 29.2% 0.8 (P = 0.013) was risk factor responsible for poor vision. Among 18 eyes that were examined for visual field, glaucomatous visual field loss was found in 14 eyes (77.7%). Early-stage defect was seen in 42.8%, intermediate-stage in 28.6%, and late-stage in 28.6% of eyes. Hyphema was found in 14 eyes (42.4%). However, hyphema in 10 out of 14 eyes (71.4%) was absorbed in just one day. Therefore, hyphema should not be considered as a high risk for surgical failure (P = 0.795). CONCLUSIONS: Trabeculotomy had a high success rate in treatment of primary congenital glaucoma with fewer complications during the follow-up time. Observation from repeated operations also showed satisfactory results. Therefore, the optimal goal in preserving useful visual acuity and visual field is to obtain better control of glaucoma with trabeculotomy and treatment of amblyopia.

Risk factors of acute pancreatitis in the elderly Chinese population: a population-based cross-sectional study.

OBJECTIVE: Lifestyle changes have led to an increasing incidence of acute pancreatitis (AP) in China. The aims of this study were to evaluate the association between lifestyle as well as medical history and AP in the elderly population and to provide evidence towards the prevention against AP. METHODS: A population-based cross-sectional study was conducted in Daqing, Heilongjiang Province, China. A total of 23 294 residents aged ≥55 years were enrolled in the study. A questionnaire survey was conducted to collect data on participants' characteristics, lifestyle and medical history via a face-to-face interview, and compared these data with the medical chart. RESULTS: In total, 45 participants had been diagnosed with AP, that is, a prevalence of 0.19%. No significant differences were observed with respect to their age, gender, marital status or body mass index (BMI) in participants with and without AP. However, those were better educated were more likely to develop AP (P = 0.005). The univariate analysis showed that a high meat intake, smoking, alcohol consumption and a medical history of gallstones were associated with a significant increase in the risk of developing AP (P < 0.05). Furthermore, smoking or alcohol consumption was dose-dependently associated with the risk of AP, particularly in those who smoked at least 15 pack-years or consumed ≥56.2 drinks per year. Multivariable logistics analysis suggested that the level of education, smoking and medical history of gallstone are independent risk factors for AP. CONCLUSIONS: Our study indicated that a higher education level, smoking, alcohol consumption and history of gallstones may be potential risk factors for AP in the elderly in northeast China.

[Effects of high and low shear stress on vascular remodeling and endothelial vascular cell adhesion molecular-1 expression in mouse abdominal aorta].

OBJECTIVE: To establish a mouse model of abdominal aorta stenosis and analyze the alterations in the arterial wall response to high and low shear stress. METHODS: Twenty mouse were randomized equally into 4 groups, including 3 test groups (1, 7 and 14 day groups) with surgically induced stenosis of the abdominal aorta, and a sham-operated group without stenosis. The hemodynamics and the internal diameter of the blood vessel were measured by color Doppler flow imaging. The wall shear stress was calculated by Poiseiulle hydrodynamics formula (τ(m)=η×4×V(m)/D). Pathological examination and immunohistochemistry were performed to observe the arterial morphological changes and the endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. The intimal-media thickness of the aorta was measured and endothelial VCAM-1 expression analyzed quantitatively. RESULTS: Regions of low and high flow shear stress were created upstream from the stenosis and within the stenosis, respectively. Compared with the sham-operated group, the mice with aorta stenosis showed gradually increased vascular intimal-media thickness and VCAM-1 expression intensity in the upstream aorta, but not within the regions of the stenosis. CONCLUSION: Vascular remodeling may occur shortly after exposure to low shear stress, which plays a significant role in initiation and progression of the pathological process of atherosclerosis mediated by VCAM-1, whereas high shear stress may exert an anti-atherosclerotic effect.

[Relationship between myocardial systolic, diastolic functions and perfusion in coronary artery stenosis].

OBJECTIVE: To evaluate the relationship between myocardial systolic, diastolic functions and perfusion in coronary artery stenosis using velocity vector imaging (VVI) and myocardial contrast echocardiography (MCE). METHODS: Stenoses in the anterior descending branch of the coronary artery were induced in 8 dogs. Before and after coronary artery stenosis, two-dimensional images of the left ventricular mastoid muscle section on the short axis at rest and in the peak dose of dobutamine were obtained for evaluation of VVI and MCE. The myocardial blood flow A.beta values, peak systolic strain rate (SRsys) and peak diastolic strain rate (SRdia) in the direction of the circumference of the short axis were measured. RESULTS: At rest, only severe coronary stenosis resulted in significantly lowered SRsys, SRdia and A.beta value of the stenotic bed compared to the values before the stenosis (-1.1-/+0.50 vs -1.62-/+0.50, 1.19-/+0.48 vs 1.75-/+0.51, 0.4-/+0.21 vs 0.80-/+0.47, P<0.05). In stress, SRsys, SRdia and A.beta value of the stenotic bed gradually decreased as coronary stenosis worsened (-4.31-/+1.14 vs -3.20-/+0.98 vs -1.18-/+0.64, 4.51-/+1.13 vs 3.39-/+0.98 vs 1.37-/+0.64. 3.54-/+1.95 vs 1.81-/+0.89 vs 0.82-/+0.42, P<0.05). Both at rest and in stress, good correlations were noted between SRsys and SRdia (r(rest)=0.88, r(stress)=0.96, P<0.01), between SRsys and the standard A.beta values (r(rest)0.56, r(stress)=0.71, P<0.01), and between SRdia and A.beta (r(rest)=0.57, r(stress)=0.72, P<0.01) in the direction of the circumference of the short axis. CONCLUSIONS: Using VVI and MCE, the changes in myocardial perfusion and the systolic and diastolic functions in the direction of the circumference can be observed dynamically. VVI may help assess the condition of myocardial perfusion by evaluating the systolic and diastolic function.