Diffusion-driven fabrication of calcium and phosphorous-doped zinc oxide heterostructures on titanium to achieve dual functions of osteogenesis and preventing bacterial infections.

Conventional Ti-based implants are vulnerable to postsurgical infection and improving the antibacterial efficiency without compromising the osteogenic ability is one of the key issues in bone implant design. Although zinc oxide (ZnO) nanorods grown on Ti substrates hydrothermally can improve the antibacterial properties, but cannot meet the stringent requirements of bone implants, as rapid degradation of ZnO and uncontrolled leaching of Zn2+ are detrimental to peri-implant cells and tissues. To solve these problems, a lattice-damage-free method is adopted to modify the ZnO nanorods with thin calcium phosphate (CaP) shells. The Ca and P ions from the CaP shells diffuse thermally into the ZnO lattice to prevent the ZnO nanorods from rapid degradation and ensure the sustained release of Zn2+ ions as well. Furthermore, the designed heterostructural nanorods not only induce the osteogenic performances of MC3T3-E1 cells but also exhibit excellent antibacterial ability against S. aureus and E. coli bacteria via physical penetration. In vivo studies also reveal that hybrid Ti-ZnO@CaP5 can not only eradicates bacteria in contact, but also provides sufficient biocompatibility without causing excessive inflammation response. Our study provides insights into the design of multifunctional biomaterials for bone implants. STATEMENT OF SIGNIFICANCE: • A lattice-damage-free method is adopted to modify the ZnO nanorods with thin calcium phosphate (CaP) shells. • The dynamic process of Ca and P diffusion into the ZnO lattice is analyzed by experimental verification and theoretical calculation. • The degradation rate of ZnO nanorods is significantly decreased after CaP deposition. • The ZnO nanorods after CaP deposition can not only sterilize bacteria in contact via physical penetration, but also provide sufficient biocompatibility and osteogenic capability without causing excessive inflammation response..

Correction: Tuning the arrangement of lamellar nanostructures: achieving the dual function of physically killing bacteria and promoting osteogenesis.

Correction for 'Tuning the arrangement of lamellar nanostructures: achieving the dual function of physically killing bacteria and promoting osteogenesis' by Shi Mo et al., Mater. Horiz., 2023, 10, 881-888, https://doi.org/10.1039/d2mh01147f.

Tuning the arrangement of lamellar nanostructures: achieving the dual function of physically killing bacteria and promoting osteogenesis.

Bacteria killing behavior based on physical effects is preferred for biomedical implants because of the negligible associated side effects. However, our current understanding of the antibacterial activity of nanostructures remains limited and, in practice, nanoarchitectures that are created on orthopedics should also promote osteogenesis simultaneously. In this study, tilted and vertical nanolamellar structures are fabricated on semi-crystalline polyether-ether-ketone (PEEK) via argon plasma treatment with or without pre-annealing. The two types of nanolamellae can physically kill the bacteria that come into contact with them, but the antibacterial mechanisms between the two are different. Specifically, the sharp edges of the vertically aligned nanolamellae can penetrate and damage the bacterial membrane, whereas bacteria are stuck on the tilted nanostructures and are stretched, leading to eventual destruction. The tilted nanolamellae are more desirable than the vertically aligned ones from the perspective of peri-implant bone regeneration. Our study not only reveals the role of the arrangement of nanostructures in orthopedic applications but also provides new information about different mechanisms of physical antibacterial activity.

Maintenance of multipotency of bone marrow mesenchymal stem cells on poly(ε-caprolactone) nanoneedle arrays through the enhancement of cell-cell interaction.

Mesenchymal stem cells (MSCs), with high self-renewal ability and multipotency, are commonly used as the seed cells for tissue engineering. However, the reduction and loss of multipotential ability after necessary expansion in vitro set up a heavy obstacle to the clinical application of MSCs. Here in this study, we exploit the autologous crystallization ability of biocompatible poly (ε-caprolactone) (PCL) to obtain uniformly distributed nanoneedle arrays. By controlling the molecular weight of PCL, nanoneedle with a width of 2 µm and height of 50 nm, 80 nm, and 100 nm can be successfully fabricated. After surface chemical modification with polydopamine (PDA), the water contact angle of the fabricated PCL nanoneedle arrays are reduced from 84° to almost 60° with no significant change of the nanostructure. All the fabricated substrates are cultured with bone marrow MSCs (BMMSCs), and the adhesion, spreading, proliferation ability and multipotency of cells on different substrates are investigated. Compared with the BMMSCs cultured on pure PCL nanoneedle arrays, the decoration of PDA can improve the adhesion and spreading of cells and further change them from aggregated distribution to laminar distribution. Nevertheless, the laminar distribution of cultured cells leads to a weak cell-cell interaction, and hence the multipotency of BMMSCs cultured on the PCL-PDA substrates is decimated. On the contrary, the pure PCL nanoneedle arrays can be used to maintain the multipotency of BMMSCs via clustered growth, and the PCL1 nanoneedle array with a height of 50 nm is more promising than the other 2 with regard to the highest proliferation rate and best multipotential differentiation ability of cultured cells. Interestingly, there is a positive correlation between the strength of cell-cell interaction and the multipotency of stem cells in vitro. In conclusion, we have successfully maintained the multipotency of BMMSCs by using the PCL nanoneedle arrays, especially the PCL1 nanoneedle array with a height of 50 nm, as the substrates for in vitro extension, and further revealed the importance of cell-cell interaction on the multipotency of MSCs. The study provides a theoretical basis for the behavioral regulation of MSCs, and is instructive to the design of tissue engineering scaffolds.

Programmed surface on poly(aryl-ether-ether-ketone) initiating immune mediation and fulfilling bone regeneration sequentially.

The immune responses are involved in every stage after implantation but the reported immune-regulated materials only work at the beginning without fully considering the different phases of bone healing. Here, poly(aryl-ether-ether-ketone) (PEEK) is coated with a programmed surface, which rapidly releases interleukin-10 (IL-10) in the first week and slowly delivers dexamethasone (DEX) up to 4 weeks. Owing to the synergistic effects of IL-10 and DEX, an aptly weak inflammation is triggered within the first week, followed by significant M2 polarization of macrophages and upregulation of the autophagy-related factors. The suitable immunomodulatory activities pave the way for osteogenesis and the steady release of DEX facilitates bone regeneration thereafter. The sequential immune-mediated process is also validated by an 8-week implementation on a rat model. This is the first attempt to construct implants by taking advantage of both immune-mediated modulation and sequential regulation spanning all bone regeneration phases, which provides insights into the fabrication of advanced biomaterials for tissue engineering and immunological therapeutics.

A more defective substrate leads to a less defective passive layer: Enhancing the mechanical strength, corrosion resistance and anti-inflammatory response of the low-modulus Ti-45Nb alloy by grain refinement.

Orthopedic and dental implants made of ß-type Ti alloys have low elastic modulus which can better relieve the stress shielding effects after surgical implantation. Nevertheless, clinical application of ß-type Ti alloys is hampered by the insufficient mechanical strength and gradual release of pro-inflammatory metallic ions under physiological conditions. In this study, the ß-type Ti-45Nb alloy is subjected to high-pressure torsion (HPT) processing to refine the grain size. After HPT processing, the tensile strength increases from 370 MPa to 658 MPa due to grain boundary strengthening and at the same time, the favorable elastic modulus is maintained at a low level of 61-72 GPa because the single ß-phase is preserved during grain refinement. More grain boundaries decrease the work function and facilitate the formation of thicker and less defective passive films leading to better corrosion resistance. In addition, more rapid repair of the passive layer mitigates release of metallic ions from the alloy and consequently, the inflammatory response is suppressed. The results reveal a strategy to simultaneously improve the mechanical and biological properties of metallic implant materials for orthopedics and dentistry. STATEMENT OF SIGNIFICANCE: The low modulus Ti-45Nb alloy is promising in addressing the complication of stress shielding induced by biomedical Ti-based materials with too-high elastic modulus. However, its insufficient strength hampers its clinical application, and traditional strengthening via heat treatments will compromise the low elastic modulus. In the current study, we enhanced the ultimate tensile strength of Ti-45Nb from 370 MPa to 658 MPa through grain-refinement strengthening, while the elastic modulus was maintained at a low value (61-72 GPa). Moreover, substrate grain-refinement has been proved to improve the corrosion resistance of Ti-45Nb with reduced inflammatory response both in vitro and in vivo. A relationship between the substrate microstructure and the surface passive layer has been established to explain the beneficial effects of substrate grain-refinement.

Enhanced interfacial adhesion and osseointegration of anodic TiO2 nanotube arrays on ultra-fine-grained titanium and underlying mechanisms.

The poor adhesion of anodic TiO2 nanotubes (TNTs) arrays on titanium (Ti) substrates adversely affects applications in many fields especially biomedical engineering. Herein, an efficient strategy is described to improve the adhesion strength of TNTs by performing grain refinement in the underlying Ti substrate via high-pressure torsion processing, as a larger number of grain boundaries can provide more interfacial mechanical anchorage. This process also improves the biocompatibility and osseointegration of TNTs by increasing the surface elastic modulus. The TNTs in length of 0.4 µm have significantly larger adhesion strength than the 2.0 µm long ones because the shorter TNTs experience less interfacial internal stress. However, post-anodization annealing reduces the fluorine concentration in TNTs and adhesion strength due to the formation of interfacial cavities during crystallization. The interfacial structure of TNTs/Ti system and the mechanism of adhesion failures are further investigated and discussed. STATEMENT OF SIGNIFICANCE: Self-assembled TiO2 nanotubes (TNTs) prepared by electrochemical anodization have a distinct morphology and superior properties, which are commonly used in photocatalytic systems, electronic devices, solar cells, sensors, as well as biomedical implants. However, the poor adhesion between the TNTs and Ti substrate has hampered wider applications. Here in this study, we describe an efficient strategy to improve the adhesion strength of TNTs by performing grain refinement in the underlying Ti substrate via high-pressure torsion (HPT) processing. The interfacial structure of TNTs/Ti system and the mechanism of adhesion failure are systematically studied and discussed. Our findings not only develop the knowledge of TNTs/Ti system, but also provide new insights into the design of Ti-based implants for orthopedic applications.

Nonleaching Antibacterial Concept Demonstrated by In Situ Construction of 2D Nanoflakes on Magnesium.

In bone implants, antibacterial biomaterials with nonleaching surfaces are superior to ones based on abrupt release because systemic side effects arising from the latter can be avoided. In this work, a nonleaching antibacterial concept is demonstrated by fabricating 2D nanoflakes in situ on magnesium (Mg). Different from the conventional antibacterial mechanisms that depend on Mg2+ release and pH increase, the nanoflakes exert mechanical tension onto the bacteria membranes to destroy microorganisms on contact and produce intracellular stress via physical interactions, which is also revealed by computational simulations. Moreover, the nanoflake layer decelerates the corrosion process resulting in mitigated Mg2+ release, weaker alkalinity in the vicinity, and less hydrogen evolution, in turn inducing less inflammatory reactions and ensuring the biocompatibility as confirmed by the in vivo study. In this way, bacteria are killed by a mechanical process causing very little side effects. This work provides information and insights pertaining to the design of multifunctional biomaterials.

Tuning the surface immunomodulatory functions of polyetheretherketone for enhanced osseointegration.

The adverse macrophage-mediated immune response elicited by the surface of polyetheretherketone (PEEK) is responsible for the formation of fibrous encapsulation and resulting inferior osseointegration of PEEK implants in the dental and orthopedic fields. Therefore, endowing the PEEK surface with immunomodulatory ability is an appealing strategy to enhance implant-bone integration. Herein, a reliable and cost-effective method to construct adherent films with tunable nanoporous structures on PEEK is described. The functionalized surface not only suppresses the acute inflammatory response of macrophages, but also provides a favorable milieu for osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). Whole genome expression analysis reveals that the suppression effect arises from synergistic inhibition of focal adhesion, Toll-like receptor, and NOD-like receptor signaling pathways, as well as the attenuating loop through the JAK-STAT and TNF signaling pathways in macrophages. Further in vivo studies confirm that the functionalized surface induces less fibrous capsule formation and an improved bone regeneration. The nanoporous films fabricated on PEEK harmonize the early macrophage-mediated inflammatory response and subsequent hBMSCs-centered osteogenic functions consequently yielding superior osseointegration.

Catechol/polyethyleneimine conversion coating with enhanced corrosion protection of magnesium alloys: potential applications for vascular implants.

Magnesium (Mg) alloys are promising biodegradable materials but challenges remain due to their rapid degradation, especially in the potential use of Mg alloys as vascular stents. Surface modification techniques are the most straightforward way to address both the desired biocompatibility and inhibit the corrosion of Mg alloys. In this work, inspired by the functional moieties (catechols) of mussel adhesive proteins, a mimetic approach to construct organic protective conversion coatings on magnesium-zinc-manganese (MgZnMn) alloys is investigated. Based on the cross-linking of CA (catechol) and PEI (polyethyleneimine), a CA/PEI conversion coating is developed on a MgZnMn alloy. The CA/PEI conversion coating showed enhanced corrosion resistance due to the strong binding and aggregation of units. Moreover, such coatings could also provide enough primary amine groups, catechols and quinones, which can be used to immobilize further molecules. Heparin was further grafted onto the CA/PEI, endowing the conversion coating with the desired functionality. Vascular cell behavior on such a coating is also studied. The improved hemocompatibility, favorable anti-inflammatory ability, suppressed smooth muscle cell proliferation and enhanced endothelialization indicate the potential of such organic conversion coatings on MgZnMn alloys as vascular implants.

Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.

BACKGROUND: This is an update of the original Cochrane Review published in Cochrane Library, Issue 10, 2012.Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear. OBJECTIVES: To evaluate the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy. To investigate whether any subgroup of women with HM may benefit more from P-Chem than others. SEARCH METHODS: For the original review we performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and Embase (1980 to 2012, week 9). We developed the search strategy using free text and MeSH. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 5, 2017), MEDLINE (February 2012 to June week 1, 2017) and Embase (February 2012 to 2017, week 23). We also handsearched reference lists of relevant literature to identify additional studies and searched trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of P-Chem for HM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and extracted data using a specifically designed data collection form. Meta-analyses were performed by pooling data from individual trials using Review Manager 5 (RevMan 5) software in line with standard methodological procedures expected by Cochrane methodology. MAIN RESULTS: The searches identified 161 records; after de-duplication and title and abstract screening 90 full-text articles were retrieved. From these we included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality.P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; risk ratio (RR) 0.37, 95% confidence interval (CI) 0.24 to 0.57; I² = 0%; P < 0.00001; low-quality evidence). However, owing to the poor quality (high risk of bias) of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28, 95% CI 0.10 to 0.73; P = 0.01); therefore we consider this evidence to be of low quality.The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72, 95% CI 13.19 to 44.24; P = 0.0003; low-quality evidence); and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10, 95% CI 0.52 to 1.68; P = 0.0002; very low quality evidence).There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes. AUTHORS' CONCLUSIONS: P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delays treatment of GTN and may expose women toxic side effects, this practice cannot currently be recommended.

Heparin/DNA aptamer co-assembled multifunctional catecholamine coating for EPC capture and improved hemocompatibility of vascular devices.

Good hemocompatibility and rapid endothelialization are two key factors in the success of stent interventional therapy. In this study, aptamers with the ability to capture endothelial progenitors and anticoagulant molecular heparin were successfully immobilized on the surface of dopamine/polyethylenimine (PDA/PEI) copolymer coating via electrostatic interaction. The results of X-ray spectroscopy (XPS), water contact angle (WCA), and immunofluorescence staining tests confirmed the successful introduction of heparin and aptamers. Platelet adhesion and whole blood experiments demonstrated that the hemocompatibility of the co-modified surface was improved. Dynamic endothelial progenitor cell (EPC) capture experiments showed that the modified surfaces could effectively capture the endothelial progenitor in dynamic conditions. More importantly, ex vivo experiments revealed that the modified surfaces could regulate the distribution of CD34/vWF-positive cells on stent surfaces, and this was beneficial for the endothelialization of vascular stents. These results suggested that heparin and aptamer co-modified stents could capture EPCs and promote endothelialization. This surface co-modification strategy has great potential for enhancing stent development.

Stability research on polydopamine and immobilized albumin on 316L stainless steel.

In this study, the polydopamine (PDA) film was coated on polished 316Lss and then thermally treated at 150 °C (labeled as PDA-Th150), and the stability of coatings was also investigated. Straining test indicated that PDA-Th150 coating performed better in affording sufficient adherence to 316 L SS substrate. Moreover, both PDA and PDA-Th150 coating suffered slight swelling during immersion in deionized water (pH = 6.5). X-ray photoelectron spectroscopy results showed that during immersion, latent nucleophilic reaction via amines inside PDA coating occurred. This led to an enhanced cross-linking and thus gradually promoted the coating stability. Moreover, larger amount of bovine serum albumin (BSA) was immobilized onto PDA-Th150 coating and performed well in anti-platelet adhesion. A high retention of immobilized BSA was observed even after immersion for 30 days. These tests suggested that PDA was stable enough and performed well in surface functionalization, which might enrich the research and application of PDA.

Multifunctional mussel-inspired copolymerized epigallocatechin gallate (EGCG)/arginine coating: the potential as an ad-layer for vascular materials.

Surface properties are considered to be important factors in addressing proper functionalities. In this paper, a multifunctional mussel-inspired coating was prepared via the direct copolymerization of epigallocatechin gallate (EGCG) and arginine. The coating formation was confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectra. The EGCG/arginine coating contained diverse functional groups like amines, phenols and carboxyls, whose densities were also tunable. Such mussel-inspired coating could also be applied as an ad-layer for its secondary reactivity, demonstrated by quartz crystal microbalance technique. Moreover, the tunable surface density of phenols showed potential ability in modulating endothelial cell and smooth muscle cell viability. The coatings rich in phenols presented excellent free radical scavenging property. Current results strongly indicated the potential of EGCG/arginine coatings to be applied as an ad-layer for vascular materials.

Inhibitors of differentiation-1 promotes nitrosopyrrolidine-induced transformation of HPV 16-immortalized cervical epithelial cell.

Our previous study implied a correlation between inhibitors of differentiation-1 (Id-1) and cervical cancer development. However, how Id-1 contributes to cervical carcinogenesis is unknown. In the present study, we used an in vitro transformation model to investigate the role of Id-1 in the transformation of cervical cells. Human papillomavirus (HPV)-immortalized cervical epithelial cells (H8) were successfully transformed by exposure to the carcinogen N-nitrosopyrrolidine (NPYR). The expression of both Id-1 RNA and protein was significantly increased in transformed H8 cells, suggesting a possible role of Id-1 in cervical cell transformation. Ectopic expression of Id-1 in H8 cells potentiated NPYR-induced cell transformation. In contrast, silencing of Id-1 suppressed NPYR-induced H8 cell transformation. In addition, the expression of HPV E6 and E7 oncoproteins was upregulated while that of the tumor suppressors p53 and pRb was suppressed after H8 cell transformation. Our results suggest that Id-1 plays an oncogenic role in HPV-related cervical carcinogenesis, which sheds light on cervical cancer development mechanisms and implies that Id-1 is a potential target for cervical cancer prevention and therapy.

[Effects of NF-kappaB inhibitor on cisplatin-induced apoptosis in cervical cancer].

OBJECTIVE: To observe whether cisplatin-induced apoptosis were increased when SiHa cells were preincubated with nuclear factor-kappa B (NF-kappaB) inhibitors [aspirin, sulindac, curcumin or pyrrolidine dithiocarbamate (PDTC)]. METHODS: SiHa cells were preincubated 2 hours with aspirin, sulindac, curcumin and PDTC respectively, then a further incubation were done with cisplatin, and Western blot analysis were applied to detect P65 level of nuclear extraction. MTT assay was done to detect relative cell viability. TUNEL was applied to detect apoptosis rates. Flow cytometryies with PI staining were also used to detect apoptosis as well as cell cycle. RESULTS: When SiHa cells were pretreated with aspirin, sulindac, curcumin or PDTC, Western blot showed that the expression of P65 was inhibited upon cisplatin stimulus (P < 0.05). MTT assay demonstrated that a preincubation with NF-kappaB inhibitor could signifianctly increase cisplatin-induced chemosensitivity (P < 0.05). When cells pretreated with aspirin, sulindac, curcumin, or PDTC, TUNEL and flow cytometries assay showed that the apoptotic rates were all increased after 24 hours cisplatin stimulus (P < 0.05). Results of flow cytometries were also showed that a pretreation with aspirin, sulindac, curcumin, or PDTC could significantly increase cisplatin-induced apoptosis. CONCLUSION: Aspirin, sulindac, curcumin and PDTC could all inhibit cisplatin induced NF-kappaB activiation, which could increase cispaltin-induced chemosensativity by augments of apoptosis.

Selective estrogen receptor modulators (SERMs) for uterine leiomyomas.

BACKGROUND: Uterine fibroids are benign tumours that arise from individual smooth muscle cells of the uterus. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that act as estrogens in some tissues while blocking estrogen activity in others. There have been many clinical studies of various SERMs for uterine fibroids. However, their effectiveness is controversial. OBJECTIVES: To evaluate the effectiveness and safety of selective estrogen receptor modulators in women with uterine fibroids. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, EMBASE, the Register of Chinese trials developed by the Chinese Cochrane Centre, and the Chinese Med Database (Chinese Biomedical Disc), VIP, and China National Knowledge Infrastructure. We handsearched a number of journals and searched reference lists, and searched databases of ongoing trials and the Internet. The searches were conducted in March and April 2012. SELECTION CRITERIA: We included randomised controlled studies of selective estrogen receptor modulators versus other forms of medical therapy, placebo or no treatment in women of reproductive age (18 to 45 years old) with confirmed uterine fibroids. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. As the studies identified were not sufficiently similar, we did not do a meta-analysis but summarised the data in a narrative format. MAIN RESULTS: Three studies involving 215 participants were included, the trial size varied from 25 to 100 women. The SERM in all cases was raloxifene. In one study women in both arms received gonadotrophin releasing hormone (GnRH) analogue. Comparison interventions included no treatment and placebo. Two of the three included studies found a significant benefit from raloxifene, but the third study found no benefit at three or six-month follow-up. The overall quality of the evidence was low or very low. All three studies mentioned adverse reactions but data were limited. AUTHORS' CONCLUSIONS: There is no consistent evidence from the limited number of studies that SERMs reduce the size of fibroids or improve clinical outcomes. Further studies are required to establish evidence of benefit of SERMs in treating women with uterine fibroids. This updated review did not find any new study for inclusion.

Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.

BACKGROUND: Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear. OBJECTIVES: To systematically review the evidence for the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy. SEARCH METHODS: We performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and EMBASE (1980 to week 9, 2012). The search strategy was developed using free text and medical subject headings (MESH). We handsearched reference lists of relevant literature to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of P-Chem for HM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and extracted data using a specifically designed data collection form. Meta-analyses were performed by pooling data from individual trials using RevMan 5.1 software. MAIN RESULTS: We included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality.P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; RR 0.37; 95% confidence interval (CI) 0.24 to 0.57; I(2) = 0%; P < 0.00001), However, owing to the poor quality of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28; 95% CI 0.10 to 0.73; P = 0.01), therefore we consider this evidence to be of a low quality.The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72; 95% CI 13.19 to 44.24; P = 0.0003) and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10; 95% CI 0.52 to 1.68; P = 0.0002). We consider this evidence to be of a low to very low quality for similar reasons to those listed above.There were insufficient data to perform meta-analyses for toxicity, overall survival, drug resistance and reproductive outcomes. AUTHORS' CONCLUSIONS: P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delay treatment of GTN and expose women unnecessarily to toxic side effects, this practice cannot currently be recommended.

Association of inhibitor of differentiation 1 expression with human papillomaviruses infections in cervical carcinoma.

BACKGROUND: Our recent study has shown that inhibitor of differentiation 1 (Id-1) is overexpressed in cervical carcinoma. However, the relationship between Id-1 expression and human papillomavirus (HPV) infection has not been elucidated. In this study, we investigate the association of Id-1 protein expression and HPV infection in cervical carcinoma tissues. METHODS: A total of 56 paraffin-embedded and 12 fresh cervical carcinoma tissues were collected for Id-1 and HPV detection. The Id-1 protein was detected by immunohistochemistry and Western blot in paraffin-embedded and fresh carcinoma tissues. Human papillomavirus DNA was detected and genotyped by using an oligonucleotide microarray and polymerase chain reaction. RESULTS: The overall HPV prevalence was 82.1%, whereas that of HPV type 16 (HPV-16) was 62.5% in cervical carcinoma. The HPV-positive samples showed higher Id-1 expression levels than the HPV-negative ones (Cochran-Mantel-Haenszel χ test [χCMH] = 4.39, P < 0.05). The HPV-16-infected samples had higher Id-1 expression levels than the samples with infection of other single HPV genotypes (χCMH = 6.42, P < 0.02). The results of Western blot were correlated to the immunohistochemistry results, showing a higher Id-1 expression level in HPV-infected especially HPV-16-infected carcinoma tissues. CONCLUSIONS: Inhibitor of differentiation 1 expression is correlated to HPV infection in cervical carcinoma, suggesting that Id-1 plays a role in HPV-related cervical carcinogenesis.

Association of constitutive nuclear factor-kappaB activation with aggressive aspects and poor prognosis in cervical cancer.

INTRODUCTION: Although nuclear factor-kappaB (NF-kappaB) is generally believed to be involved in carcinogenesis, the relationship between NF-kappaB activation and progression of cervical cancer in clinical settings has not been reported. In this study, we investigated the association of NF-kappaB activation with aggressive aspects and prognosis in cervical cancer. METHODS: Nuclear factor-kappaB subunits p65 and p50 were detected in 159 paraffin tissues including normal cervical, precancerous (squamous intraepithelial lesions), and cervical carcinoma tissues by immunohistochemistry. Nuclear factor-kappaB nuclear translocation and DNA-binding activity in precancerous or carcinoma tissues were examined by Western blot and electrophoretic mobility shift assay, respectively. RESULTS: A gradual NF-kappaB activation from normal cervical epithelial cells to precancerous and carcinoma cells was detected by immunohistochemistry (nuclear expression of p65 and p50, P < 0.001), Western blot (NF-kappaB nuclear translocation), and electrophoretic mobility shift assay (enhanced DNA-binding activity). In 79 cancer tissues, increased nuclear p65, an active NF-kappaB form, was correlated with poor tumor grade, lymphatic metastasis, interstitial invasion, and larger tumor size (P < 0.05). Similarly, increased nuclear p50 was correlated with poor tumor grade, interstitial invasion, and larger tumor size (P < 0.05). Moreover, increased nuclear p65 was associated with lower survival rate in patients with cancer (P < 0.05). CONCLUSIONS: Constitutive NF-kappaB activation is correlated to tumor progression, aggressive behaviors, and poor prognosis in cervical cancer, suggesting that NF-kappaB is a tumor promoter, a prognostic indicator, and a possible therapeutic target for this malignant disease.