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The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.
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Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/química , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/química , Quinolinas/química , Quinolinas/farmacología , Transportadoras de Casetes de Unión a ATP/metabolismo , Regulación Alostérica/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Escherichia coli/química , Hidrocarburos/química , Hidrocarburos/metabolismo , Lipopolisacáridos/química , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Modelos Moleculares , Dominios Proteicos/efectos de los fármacosRESUMEN
We propose an infrared-sensitive negative differential transconductance (NDT) phototransistor based on a graphene/WS2/Au double junction with a SiO2/Ge gate. By changing the drain bias, diverse field-effect characteristics can be achieved. Typical p-type and n-type behavior is obtained under negative and positive drain bias, respectively. And NDT behavior is observed in the transfer curves under positive drain bias. It is believed to originate from competition between the top and bottom channel currents in stepped layers of WS2 at different gate voltages. Moreover, this phototransistor shows a gate-modulated rectification ratio of 0.03 to 88.3. In optoelectronic experiments, the phototransistor exhibits a responsivity of 2.76 A/W under visible light at 532â nm. By contrast, an interesting negative responsivity of -29.5 µA/W is obtained and the NDT vanishes under illumination by infrared light at 1550â nm. A complementary inverter based on two proposed devices of the same structure is constructed. The maximum voltage gain of the complementary inverter reaches 0.79 at a supply voltage of 1.5â V. These results demonstrate a new method of realizing next-generation two- and three-dimensional electronic and optoelectronic multifunctional devices.
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Predicting solubility of small molecules is a very difficult undertaking due to the lack of reliable and consistent experimental solubility data. It is well known that for a molecule in a crystal lattice to be dissolved, it must, first, dissociate from the lattice and then, second, be solvated. The melting point of a compound is proportional to the lattice energy, and the octanol-water partition coefficient (log P) is a measure of the compound's solvation efficiency. The CCDC's melting point dataset of almost one hundred thousand compounds was utilized to create widely applicable machine learning models of small molecule melting points. Using the general solubility equation, the aqueous thermodynamic solubilities of the same compounds can be predicted. The global model could be easily localized by adding additional melting point measurements for a chemical series of interest.
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Aprendizaje Automático , Agua , Solubilidad , Agua/química , Octanoles/químicaRESUMEN
We propose the design of a composite device structure with germanium-based (Ge-based) waveguide photodetectors integrated with grating couplers on a silicon-on-insulator platform. The finite-difference time-domain method is used to establish simulation models and optimize the design of the waveguide detector and grating coupler. For the grating coupler, by adjusting the size parameters to the optimal value and combining the advantages of the nonuniform grating and the Bragg reflector structure, the peak coupling efficiency reaches 85% at 1550 nm and 75.5% at 2000 nm, which is, respectively, 31.3% and 14.6% higher than that of uniform grating. For the waveguide detector, a germanium-tin (GeSn) alloy was introduced to replace Ge as the active absorption layer at 1550 and 2000 nm, which not only broadened the detection range and significantly improved the light absorption of the detector but also realized the near-complete light absorption of the GeSn alloy when the device length was 10 µm. These results make it possible to miniaturize the device structure of Ge-based waveguide photodetectors.
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The two-dimensional/three-dimensional van der Waals heterostructures provide novel optoelectronic properties for the next-generation of information devices. Herein, MoS2/Ge heterojunction avalanche photodetectors are readily obtained. The device with an Ag electrode at MoS2 side exhibits more stable rectification characteristics than that with an Au electrode. The rectification radio greater than 103 and a significant avalanche breakdown are observed in the device. The responsivity of 170 and 4 A/W and the maximum gain of 320 and 13 are obtained under 532 and 1550 nm illumination, respectively. Such photoelectric properties are attributed to the carrier multiplication at a Ge/MoS2 junction due to an avalanche breakdown. The mechanism is confirmed by the Sentaurus TCAD-simulated I-V characteristics.
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A Ge metal-semiconductor-metal photodetector covered with asymmetric HfSe2 contact geometries has been proposed to realize high-performance unbiased photodetection at 1550 nm. At -1 V bias, the responsivity of this device shows a 71% improvement compared to the device without HfSe2. Moreover, the responsivity and detectivity of this device at zero bias can reach to 71.2 mA/W and 3.27×1010 Jones, respectively. Furthermore, the fall time of this device is 2.2 µs and 53% shorter than the device without HfSe2. This work provides a feasible way to develop unbiased Ge-based photodetectors in the near-IR communications band.
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A broadband, high-performance infrared Ge photodetector decorated with Au nanoparticles (NPs) is proposed. Photoelectronic characterization demonstrated that the responsivity of devices decorated with Au NPs is as high as 3.95 A/W at a wavelength of 1550â nm. Compared with a Ge photodetector without Au NPs, the responsivity of a device decorated with Au NPs is significantly increased, i.e., by more than 10 times in the entire range of infrared communication wavelengths, including the O, E, S, C, L, and U bands. The increase is ascribed to type-II energy-band alignment between Ge covered with Au NPs and bare Ge, instead of the localized surface-plasmon-resonance effect. The type-II energy-band alignment enhances the spatial electron-hole separation and restrains the electron-hole recombination, thus a larger photocurrent is observed. These results reflect the potential of this approach for achieving broadband, high-performance Ge photodetectors operating in the near-infrared communication band.
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OBJECTIVE: To study the ultrasonographic manifestations and clinical features of common pediatric testicular germ cell tumors (TGCT) in children. METHODS: We retrospectively analyzed the laboratory, ultrasonographic and clinical data on 92 children with TGCT diagnosed in Shanghai Children's Hospital from March 2013 to January 2019, and investigated the values of the serum alpha-fetoprotein (AFP) level and maximum diameter of tumors in the diagnosis of benign and malignant tumors using the ROC curve. RESULTS: Of the 92 cases of pediatric TGCT, 64 (69.6%) were pathologically confirmed as benign tumors, including 40 cases of teratoma (62.5%), 18 cases of epidermoid cyst (28.1%) and 6 cases of dermoid cyst (9.4%), and the other 28 (30.4%) as malignant neoplasms, including 26 cases of yolk sac tumor (YST, 92.9%) and 2 cases of mixed germ cell tumor (MGCT, 7.1%). Ultrasonography showed that 62.5% of the teratomas were cystic-solid mixed (25/40) and 32.5% solid masses (12/40), that 33.3% of the epidermoid cysts exhibited a typical sign of "onion ring" (6/18) and 22.2% that of capsular calcification (4/18), and that 42.3% of the YSTs displayed isoechoic (11/26), 30.9% hypoechoic (8/26) solid masses without calcium and 26.9% cystic anechoic lesions (7/26). Color Doppler blood flow imaging manifested abundant blood flow signals in most of the YSTs (25/26, 96.2%) but none in either the epidermoid or the dermoid cysts. The area under the ROC curve (AUC) of the serum AFP value was 0.985, with an optimal cutoff value of 124.2 ng/ml, and the sensitivity and specificity of AFP in the diagnosis of benign and malignant tumors were 92.9% and 93.7%, respectively. The AUC of the maximum diameter of the tumors was 0.796, with an optimal cutoff value of 2.7 cm, and the sensitivity and specificity of the maximum diameter of the tumors in the diagnosis of benign and malignant neoplasms were 57.1% and 93.7%, respectively. CONCLUSIONS: Ultrasonographic images have different characteristic manifestations for different pathological types of pediatric TGCT. Pediatric TGCT has a good prognosis and radical orchiectomy should be considered for the treatment of the tumors with serum AFP ≥ 124.2 ng/ml and a diameter ≥ 2.7 cm.
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Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias Testiculares/diagnóstico por imagen , Ultrasonografía , Niño , China/epidemiología , Humanos , Masculino , Estudios RetrospectivosRESUMEN
There is a critical need for new antibacterial strategies to counter the growing problem of antibiotic resistance. In Gram-negative bacteria, the outer membrane (OM) provides a protective barrier against antibiotics and other environmental insults. The outer leaflet of the outer membrane is primarily composed of lipopolysaccharide (LPS). Outer membrane biogenesis presents many potentially compelling drug targets as this pathway is absent in higher eukaryotes. Most proteins involved in LPS biosynthesis and transport are essential; however, few compounds have been identified that inhibit these proteins. The inner membrane ABC transporter MsbA carries out the first essential step in the trafficking of LPS to the outer membrane. We conducted a biochemical screen for inhibitors of MsbA and identified a series of quinoline compounds that kill Escherichia coli through inhibition of its ATPase and transport activity, with no loss of activity against clinical multidrug-resistant strains. Identification of these selective inhibitors indicates that MsbA is a viable target for new antibiotics, and the compounds we identified serve as useful tools to further probe the LPS transport pathway in Gram-negative bacteria.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Lipopolisacáridos/metabolismo , Antibacterianos/farmacología , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Escherichia coli/efectos de los fármacosRESUMEN
OBJECTIVE: To explore the ultrasonographic characteristics of testis tumor in children of different ages. METHODS: We retrospectively analyzed the clinical data, ultrasonographic results, surgical methods and pathological findings of 76 children with testis tumor treated in Shanghai Children's Hospital between April 2013 and March 2018. According to the age at the first diagnosis, we divided the patients into a 0ï¼4 yr (n = 57) and a 5ï¼12 yr group (n = 19), and compared the clinical manifestations, tumor markers, ultrasonographic features such as the tumor size, echogenicity, calcification and color flow images, pathological findings, and surgical methods between the two groups of patients. RESULTS: Benign tumors were found in 73.4% of the 76 children and in 100% of the patients in the 5ï¼12 yr group, with epidermoid cyst as the most common type (52.6% ï¼»10/19ï¼½), 47.4% (9/19) found accidentally, 94.7% (9/19) without elevation of the alpha-fetoprotein (AFP) level, and 94.7% (9/19) treated by testis-sparing surgery (TSS). In the 0ï¼4 yr group, teratoma and yolk sac tumors were the most common and 87.7% (50/57) of the cases were characterized by painless scrotal swelling with a normal or elevated AFP level, treated by TSS or radical orchiectomy. There were statistically significant differences between the two groups of patients in the clinical manifestations, AFP values, pathological findings and surgical methods (all P < 0.05), but not in the ultrasonographic results, mostly solid or mixed cystic-solid masses (χ2 = 0.908, P = 0.635). The maximum diameter of the tumors was smaller and the volume of the healthy contralateral testis was greater in the 5ï¼12 yr than in the 0ï¼4 yr group (t = 2.673 and 2.858, P = 0.009 and 0.010). The proportions of the tumors with calcification and those with grade 0 blood flow were significantly higher in the former than in the latter group (χ2 = 4.825 and 12.298, P = 0.028 and 0.006). CONCLUSIONS: Testis tumors have different clinical and ultrasonographic features in children of different age groups, malignancy mostly in 0- to 4-year-olds while benignancy commonly in 5- to 12-year-olds, frequently with normal AFP, calcification, and less abundant color blood flow. TSS is recommended for the treatment of testis tumor with serum AFP negative in 5ï¼12 years old children.
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Orquiectomía , Teratoma , Neoplasias Testiculares , Niño , Preescolar , China , Humanos , Lactante , Masculino , Estudios Retrospectivos , Teratoma/diagnóstico , Teratoma/cirugía , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/cirugía , Testículo/cirugíaRESUMEN
OBJECTIVE: To analyze the high-frequency ultrasound image features of acute scrotum in children and explore the value of high-frequency ultrasonography in the diagnosis and differential diagnosis of the disease. METHODS: This retrospective study included 256 children aged 2 days to 14 years undergoing color Doppler ultrasonography at 2 hours to 3 days after onset of acute scrotum. We analyzed the morphology, internal echo and blood supply of the testis in comparison with the clinical and pathological results. RESULTS: Among the 256 cases, acute testicular torsion was found in 23, of which 16 were treated by complete resection the necrotic testis and the other 7 by surgical reduction of testicular torsion. Ultrasonographically, the involved testes presented different degrees of increase or decrease in volume, with uneven internal echoes, irregular hypoechoic flakes, and testicular hydrocele. Color Doppler flow imaging (CDFI) showed significant blood flow signals around the diseased testes but none within them. Acute testicular appendix torsion was found in 116 cases, in which ultrasonography manifested nodules with round or oval abnormal echoes between the upper pole of the testis and caput epididymidis, first hypoechoic and then gradually increased, heterogeneous internally. CDFI revealed enlarged epididymides and enriched testicular blood flow but no blood flow signals in the nodules. The 103 cases of acute epididymitis were ultrasonographically characterized by varied degrees of swelling of the involved epididymis with uneven internal echoes and rich blood flow signals on CDFI. Six of the cases were diagnosed as acute orchitis, with the ultrasonographic features of testicular swelling and low but uniform internal echoes, with rich blood flow signals on CDFI. Incarcerated inguinal hernia was confirmed in 15 cases, in which ultrasonography revealed intrusion of the hernia into the obviously enlarged scrotal sac with the mesentery and intestine in it, and blood flow visible on CDFI. Acute scrotal wall hematoma and edema was found in 8 cases, with the ultrasonographic characteristics of scrotal wall thickening, with visible blood flow signals on CDFI. CONCLUSIONS: High-frequency ultrasonography has a high sensitivity and specificity for acute scrotum in children, which can be applied as the first-choice clinical imaging modality and provide reliable evidence for the diagnosis and differential diagnosis of the disease.
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Enfermedades de los Genitales Masculinos/diagnóstico por imagen , Escroto/diagnóstico por imagen , Ultrasonografía Doppler en Color , Enfermedad Aguda , Adolescente , Niño , Preescolar , Diagnóstico Diferencial , Epidídimo , Epididimitis , Hernia Inguinal , Humanos , Lactante , Recién Nacido , Masculino , Orquitis , Estudios Retrospectivos , Sensibilidad y Especificidad , Torsión del Cordón Espermático , Hidrocele TesticularRESUMEN
Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.
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Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirazoles/farmacología , Piridinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Indazoles/síntesis química , Indazoles/química , Indazoles/farmacología , Ratones , Modelos Moleculares , Proteínas Proto-Oncogénicas c-pim-1/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
In this paper, a physics-based ANN assisting method for extracting transient properties of extrinsically triggering photoconductive semiconductor switches (ET-PCSSs) is proposed. It exploits the nonlinear mapping of ANN between transient current (input) and doping concentration (output). According to the basic laws of photoelectric device operating, two types of ANN models are constructed by gaussian and polynomial fitting. The mean absolute error (MAE) of forecasting transient photocurrent can be less than 10 A under low triggering optical powers, which verifies the feasibility of ANN assisting TCAD applied to PCSSs. The results are comparable to computation by Mixed-Mode simulation, yet even thousands of seconds of CPU runtime cost are saved in every period. To improve the robustness of the Poly-ANN predictor, Bayesian optimization (BO) is implemented for minimizing the curl deviation of photocurrent-time curves.
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Congenital true diphallia, complete duplicate bladder, bladder exstrophy, and anorectal malformation in a child are uncommon. Here, we present the case of a 3-year-old boy with multiple genitourinary malformation, including true diphallia, complete duplicate bladder, bladder exstrophy, epispadias, and anorectal malformation. Multi-departmental collaborative treatment for complex conditions ultimately achieved an ideal appearance for this patient. All vital signs were stable after the surgery and they remained consistent during follow-up. In such cases, surgical correction is individualized to achieve adequate urinary continence and erection with adequate esthetics.
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Si-based emitters have been of great interest as an ideal light source for monolithic optical-electronic integrated circuits (MOEICs) on Si substrates. However, the general Si-based material is a diamond structure of cubic lattice with an indirect band gap, which cannot emit light efficiently. Here, hexagonal-Ge (H-Ge) nanostructures within a light-emitting metasurface consisting of a cubic-SiGe nanodisk array are reported. The H-Ge nanostructure is naturally formed within the cubic-Ge epitaxially grown on Si (001) substrates due to the strain-induced nanoscale crystal structure transformation assisted by far-from-equilibrium growth conditions. The direct-bandgap features of H-Ge nanostructures are observed and discussed, including a rather strong and linearly power-dependent photoluminescence (PL) peak around 1562 nm at room temperature and temperature-insensitive PL spectrum near room temperature. Given the direct-bandgap nature, the heterostructure of H-Ge/C-Ge, and the compatibility with the sophisticated Si technology, the H-Ge nanostructure has great potential for innovative light sources and other functional devices, particularly in Si-based MOEICs.
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The burgeoning need for extensive data processing has sparked enthusiasm for the development of a novel optical logic gate platform. In this study, junction field-effect phototransistors based on molybdenum disulfide/Germanium (MoS2/Ge) heterojunctions are constructed as optical logic units. This device demonstrates a positive photoresponse that is attributed to the photoconductivity effect occurring upon irradiation with visible (Vis) light. Under the illumination of near-infrared (NIR) optics with wavelengths within the communication band, the device shows a negative photoresponse, which is associated with the interlayer Coulomb interactions. The current state of the device can be effectively modulated as different logical states by precisely tuning the wavelength and power density of the optical. Within a 3 × 3 MoS2/Ge phototransistor array, five essentially all-optical logic gates ("AND," "OR," "NAND," "NOT," and "NOR") can be achieved in every signal unit. Furthermore, three complex all-optical logical operations are demonstrated by integrating two MoS2/Ge phototransistors in series. Compared to electronic designs, these all-optical logic devices offer a significant reduction in transistor number, with savings of 50-94% when implementing the above-mentioned functions. These results present opportunities for the development of photonic chips with low power consumption, high fidelity, and large volumes.
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Previous studies have reported that vitexins induce cytotoxic effects. In the present study, we investigate a new native lignan vitexin 6 (VB6) in vitro to determine the molecular mechanism underlying its cytotoxicity. We screened and cultured several tumor cell lines and subsequently analyzed VB6 cytotoxicity against 14 different tumor cell lines using a 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The expression of proteins that regulate apoptosis and autophagy was determined using western blot analysis. VB6 showed an excellent cytotoxic effect against various cancer cell lines in vitro. It induced apoptosis and autophagy of cancer cells. VB6-induced apoptosis showed a time-dependent and concentration-dependent relationship with cleaved poly (ADP-ribose) polymerase, cleaved caspase-3, Bax upregulation, and Bcl-2 downregulation. The levels of Beclin-1 and LC3-II, which are markers for cell autophagy, gradually increased after VB6 treatment. Jun N-terminal kinase (JNK) phosphorylation was increased after VB6 treatment, accompanied by upregulation of P-Bcl-2 and P-C-Jun expression. Cotreatment with a JNK inhibitor significantly decreased VB6-induced cell death and downregulated P-Bcl-2, and cleaved PARP and Beclin-1 expression. The new native lignan VB6 inhibits cancer cell proliferation by activating the JNK pathway. We believe that VB6 could be a valuable chemotherapeutic drug after further evaluation.
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Antineoplásicos Fitogénicos/farmacología , Apigenina/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lignanos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antineoplásicos Fitogénicos/antagonistas & inhibidores , Apigenina/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Etnofarmacología , Humanos , Concentración 50 Inhibidora , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/química , Cinética , Lignanos/antagonistas & inhibidores , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Semillas/química , Vitex/químicaRESUMEN
Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.
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Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirazoles/química , Pirimidinas/química , Animales , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Ratones , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
A fetus was found to have a right diaphragmatic hernia during a prenatal ultrasonography examination late in the second trimester. A "green channel" with multi department dynamic monitoring was instituted, at 40 + 4 weeks, with the infant under general anesthesia, hernia repair was later successfully performed. After the operation, the infant's vital signs were stable and their condition remained good during follow-up.
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Hernias Diafragmáticas Congénitas , Embarazo , Lactante , Femenino , Humanos , Hernias Diafragmáticas Congénitas/diagnóstico por imagen , Hernias Diafragmáticas Congénitas/cirugía , Ultrasonografía Prenatal , Ultrasonografía , Segundo Trimestre del Embarazo , FetoRESUMEN
Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC. Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab. Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30-1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04-1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41-1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07-1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73-3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49-18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46-26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47-19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59-30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84-6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios. Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].