Placental growth factor (PlGF) is an increasingly important molecule in the prediction, diagnosis and treatment of pre-eclampsia. It has pro-angiogenic effects on the feto-placental circulation and ...supports trophoblast growth. Mechanisms by which PlGF expression is regulated continue to be investigated. Low circulating PlGF precedes the manifestation of clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. This suggests that low PlGF is a marker of abnormal placentation, but it remains uncertain whether this is a cause or consequence. Prediction of pre-eclampsia using PlGF is promising and may assist in the targeting of resources to women at highest risk of adverse pregnancy outcomes. Promisingly, experimental animal models of pre-eclampsia have been successfully treated with supplemental PlGF. Treatment of pre-eclampsia with PlGF is a potential therapeutic option requiring further exploration. This review focuses specifically on the role of PlGF in normal and pathological placental development and in the clinical management of pre-eclampsia.
Abstract Extensive scientific investigations in recent decades have established the anatomical, biomechanical, and functional importance that the meniscus holds within the knee joint. As a vital part ...of the joint, it acts to prevent the deterioration and degeneration of articular cartilage, and the onset and development of osteoarthritis. For this reason, research into meniscus repair has been the recipient of particular interest from the orthopedic and bioengineering communities. Current repair techniques are only effective in treating lesions located in the peripheral vascularized region of the meniscus. Healing lesions found in the inner avascular region, which functions under a highly demanding mechanical environment, is considered to be a significant challenge. An adequate treatment approach has yet to be established, though many attempts have been undertaken. The current primary method for treatment is partial meniscectomy, which commonly results in the progressive development of osteoarthritis. This drawback has shifted research interest toward the fields of biomaterials and bioengineering, where it is hoped that meniscal deterioration can be tackled with the help of tissue engineering. So far, different approaches and strategies have contributed to the in vitro generation of meniscus constructs, which are capable of restoring meniscal lesions to some extent, both functionally as well as anatomically. The selection of the appropriate cell source (autologous, allogeneic, or xenogeneic cells, or stem cells) is undoubtedly regarded as key to successful meniscal tissue engineering. Furthermore, a large variation of scaffolds for tissue engineering have been proposed and produced in experimental and clinical studies, although a few problems with these (e.g., byproducts of degradation, stress shielding) have shifted research interest toward new strategies (e.g., scaffoldless approaches, self-assembly). A large number of different chemical (e.g., TGF-β1, C-ABC) and mechanical stimuli (e.g., direct compression, hydrostatic pressure) have also been investigated, both in terms of encouraging functional tissue formation, as well as in differentiating stem cells. Even though the problems accompanying meniscus tissue engineering research are considerable, we are undoubtedly in the dawn of a new era, whereby recent advances in biology, engineering, and medicine are leading to the successful treatment of meniscal lesions.
Significance The inadequate mechanical properties of engineered tissues have prevented related therapies from clinical translation. Collagen cross-links correlate with the mechanical integrity of ...tissues; however, addressing the weakness of neotissues through enhancing collagen cross-links has not received the attention it deserves. The present study demonstrates, both in vitro and in vivo, that improvements in the mechanical properties of native and engineered tissues can be attained using endogenous (hypoxia-mediated) and exogenous application of lysyl oxidase, which is the enzyme responsible for collagen cross-linking. By promoting an ∼16-fold increase in collagen cross-linking and, concomitantly, an approximately fivefold enhancement in the neotissue’s mechanical properties, this work creates new prospects for regenerative medicine. The methods developed here work across a spectrum of collagen-rich tissues and are clinically applicable.
The inability to recapitulate native tissue biomechanics, especially tensile properties, hinders progress in regenerative medicine. To address this problem, strategies have focused on enhancing collagen production. However, manipulating collagen cross-links, ubiquitous throughout all tissues and conferring mechanical integrity, has been underinvestigated. A series of studies examined the effects of lysyl oxidase (LOX), the enzyme responsible for the formation of collagen cross-links. Hypoxia-induced endogenous LOX was applied in multiple musculoskeletal tissues (i.e., cartilage, meniscus, tendons, ligaments). Results of these studies showed that both native and engineered tissues are enhanced by invoking a mechanism of hypoxia-induced pyridinoline (PYR) cross-links via intermediaries like LOX. Hypoxia was shown to enhance PYR cross-linking 1.4- to 6.4-fold and, concomitantly, to increase the tensile properties of collagen-rich tissues 1.3- to 2.2-fold. Direct administration of exogenous LOX was applied in native cartilage and neocartilage generated using a scaffold-free, self-assembling process of primary chondrocytes. Exogenous LOX was found to enhance native tissue tensile properties 1.9-fold. LOX concentration- and time-dependent increases in PYR content (∼16-fold compared with controls) and tensile properties (approximately fivefold compared with controls) of neocartilage were also detected, resulting in properties on par with native tissue. Finally, in vivo subcutaneous implantation of LOX-treated neocartilage in nude mice promoted further maturation of the neotissue, enhancing tensile and PYR content approximately threefold and 14-fold, respectively, compared with in vitro controls. Collectively, these results provide the first report, to our knowledge, of endogenous (hypoxia-induced) and exogenous LOX applications for promoting collagen cross-linking and improving the tensile properties of a spectrum of native and engineered tissues both in vitro and in vivo.
Abstract Background For women with oestrogen receptor+ metastatic breast cancer (MBC), the options for systemic treatment include endocrine therapy (ET) and chemotherapy. For women whose disease is ...also HER2+, anti-HER2 therapies are also routinely used either with chemotherapy or less commonly with ET. Where chemotherapy is used as initial therapy, treatment is often discontinued due to cumulative toxicity in the absence of disease progression. In this setting, there is the option of introducing ET with the aim of prolonging response and delaying relapse. Methods Literature review revealed four trials addressing the question of whether there is a benefit from introducing ET following chemotherapy for MBC. We also sought evidence for alternative approaches, including concurrent chemotherapy and ET and continuing chemotherapy until disease progression. Results The evidence for the use of ET after chemotherapy in MBC is limited, and the trials done were small. Furthermore, they were performed at a time when both the chemotherapy regimens and ET were different from those used currently. Despite these limitations, there is probably a modest improvement in time to progression for the sequential use of ET after chemotherapy but with no overall survival benefit. An alternative approach, particularly considering agents with relatively low toxicity, such as orally bioavailable fluoropyrimidines, is to continue chemotherapy until disease progression. Conclusion Where chemotherapy for MBC is discontinued due to toxicity, in the absence of progression, the use of ET, with its relatively low toxicity, is a reasonable approach with the aim of delaying relapse.
Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, ...reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.
Abstract
STUDY QUESTION
Does follicular flushing increase the number of cumulus–oocyte complexes (COCs) retrieved compared to single aspiration?
SUMMARY ANSWER
Follicular flushing significantly ...increases the number of COCs retrieved compared to single aspiration.
WHAT IS KNOWN ALREADY
On the basis of published meta-analyses, follicular flushing does not seem to increase the number of oocytes retrieved, the probability of clinical pregnancy, or that of live birth and has been associated with an increase in the duration of oocyte retrieval. It should be noted, however, that all the eligible randomized controlled trials (RCTs) in these meta-analyses have randomized patients into either single aspiration or follicular flushing. This study design might not allow the detection of the true effect of follicular flushing. Despite randomization, this might still be obscured, to an extent, by heterogeneity in patients, stimulation characteristics, and differences in the oocyte retrieval procedure.
STUDY DESIGN, SIZE, DURATION
A prospective, single centre, RCT, including 105 patients was performed between July and December 2022.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Eligible patients were those undergoing oocyte retrieval for ICSI, aged <43 years, with BMI 18–35 kg/m2. Patients with all types of ovarian response (low-normal-high), as assessed on the day of triggering final oocyte maturation, were included. Random allocation of the ovaries of each patient to either single aspiration or follicular flushing was performed on the day of oocyte retrieval, using a computer-generated randomization list. Patients could enter the study only once. All follicles from ovaries allocated to either follicular flushing or single aspiration, were aspirated by the same 16G double lumen needle, with a constant aspiration pressure of 190 mmHg, resulting in flow rate of 0.42 ml/s. In the ovaries allocated to the follicular flushing group, if a COC was not recovered in the initial aspirate of each follicle, follicular flushing was performed until a COC was retrieved, up to a maximum of five times. The primary outcome measure was the number of COCs retrieved. Secondary outcomes were oocyte recovery rate, oocyte maturation rate, fertilization rate, and rate of good quality embryos on Day 2. Values are expressed as a median (inter-quartile range).
MAIN RESULTS AND THE ROLE OF CHANCE
Significantly more COCs were retrieved in the follicular flushing as compared to the single aspiration group in all patients 5 (7) vs 2 (3), P < 0.001, respectively, as well as in patients with high 9 (3) vs 5 (4), P < 0.001, respectively, normal 5 (2) vs 2 (3), P < 0.001, respectively and low 1 (1) vs 1 (1), P < 0.001, respectively ovarian response. In patients with low ovarian response, no COCs were retrieved in 5.7% of the ovaries in the flushing group vs 42.8% of the ovaries in the single aspiration group (P < 0.001). The oocyte retrieval rate was significantly higher in the follicular flushing vs the single aspiration group, in all patients 88.9% (25.0) vs 45.5% (37.5), P < 0.001, respectively, as well as in patients with high 81.8% (15.9) vs 45.5% (22.2), P < 0.001, respectively, normal 85.7% (28.6) vs 40.0% (30.0), P < 0.001, respectively, and low 100% (0) vs 50.0% (100), P < 0.001, respectively ovarian response. No significant difference was observed regarding maturation rate 85.2% (30.8) vs 100% (33.3), P = 0.78, fertilization rate 76.4% (50) vs 83.3% (50) P = 0.42, and the proportion of good quality embryos on Day 2 83.3% (40) vs 100% (50), P = 0.62. Similarly, no differences in the above variables were observed in patients with different types of ovarian response. Follicular flushing as compared to single aspiration was associated with a significant increase in the duration of oocyte retrieval in all patients 248 s (332) vs 135 s (164), respectively, as well as in patients with high 464 s (225) vs 237 s (89), P < 0.001, respectively, normal 248 s (108) vs 141 s (95), P < 0.001, respectively, and low 64 s (59) vs 48 s (10), P < 0.001, respectively ovarian response.
LIMITATIONS, REASONS FOR CAUTION
Although the current study design allows for a more accurate evaluation of the true effect of follicular flushing on the number of COCs retrieved, it does not permit the evaluation of its role on the probability of pregnancy.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first RCT to suggest that follicular flushing increases the number of COCs retrieved compared to single aspiration, independently of ovarian response. This implies that follicular flushing plays an important role in the optimization of oocyte retrieval. These results, however, need to be confirmed in future studies, in which an equal flow rate should be used during oocyte retrieval.
STUDY FUNDING/COMPETING INTEREST(S)
No external funding was obtained for this study. There are no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
NCT05473455
TRIAL REGISTRATION DATE
15 July 2022
DATE OF FIRST PATIENT’S ENROLMENT
27 July 2022
Neoadjuvant (primary systemic) treatment has become a standard option for primary operable disease for patients who are candidates for adjuvant systemic chemotherapy, irrespective of the size of the ...tumor. Because of new treatments and new understandings of breast cancer, however, recommendations published in 2006 regarding neoadjuvant treatment for operable disease required updating. Therefore, a third international panel of representatives of a number of breast cancer clinical research groups was convened in September 2006 to update these recommendations. As part of this effort, data published to date were critically reviewed and indications for neoadjuvant treatment were newly defined.
Background: Of the 200 million patients worldwide affected by peripheral arterial disease (PAD), 4% will inevitably require major limb amputation. Previous systematic reviews presented a conflicting ...body of evidence in terms of vascular endothelial growth factor (VEGF) family member effects upon PAD natural progression. Despite that, modulation of intrinsic angiogenesis mechanisms targeting the VEGF family members still confers an attractive therapeutic target. The aim of the present study was to evaluate current evidence of VEGF modulation in the context of PAD. Methods: This is a systematic literature review conducted according to the PRISMA guidelines and registered under PROSPERO database CRD42021285988. Independent literature search was performed up to April 1, 2022, on six databases. A total of 22 eligible studies were identified N: 3, interventional patient studies; N: 19, animal studies. Animal studies were appraised by the SYRCLE risk of bias tool, while human participant studies were assessed by the Newcastle Ottawa scale. Overall, quality of evidence was deemed fair for both animal and human studies. Main study outcomes were percentage change of injured vessel lumen stenosis and neointimal area formation upon VEGF modulation (inhibition or activation) in comparison with control group. Findings: Nineteen animal models and three human participant studies were included in the systematic review and assessed separately. Positive modulation of VEGF-A in animal models resulted in a median decrease of 65.58% 95% CI 45.2; 71.87 in lumen stenosis 14 studies. Furthermore, positive modulation of VEGF-A was found to reduce neointimal area proliferation by a median decrease of 63.41% 95% CI 41.6; 79.59 14 studies. Median end of study duration was 28 days range: 14–84 days. Data were insufficient to assess these outcomes with respect to VEGF-B or VEGF-C modulation. The limited number of available human studies presented inadequate outcome assessment despite their overall fair NOS grading. Interpretation: VEGF-A-positive modulation decreases lumen stenosis and neointimal hyperplasia in PAD simulation animal models. Previously identified variability among outcomes was found to strongly stem from the variability of experimental designs. Clinical applicability and safety profile of VEGF-A in the context of PAD remain to be defined by a robust and uniformly designed body of further animal model-based experiments.
Cigarette smoking (CS) and preeclampsia (PE), regulate the expression of nicotinic acetylcholine receptor (nAChR) subunits in the placenta, yet no data exist at the histological level.
Using ...immunohistochemistry of formalin fixed and paraffin embedded placental tissue, this study quantified the expression of nine nAChR subunits (α2, α3, α4, α5, α7, α9, β1, β2, δ) and compared the expression amongst four groups of non-smoker non-PE (controls, n = 8), smokers (n = 8), PE (n = 8), and those who were smokers with PE (smoke + PE, n = 4). Quantification was of the percentage of villi with positive cells stained (% villi with +ve), percentage of positive stained cells per villous (% +ve cells/villous), percentage of positive cells in the decidua (%+ve Decidua), and intensity of staining in the outer villous trophoblast layer.
Changes were restricted to the villi (as opposed to the decidua), and were specific to the α9 (smoke + PE), β1 (smokers), and β2 (PE) subunits when compared to controls. CS seemed to have a protective effect for the β2 subunit and an additive effect for the α9 and β1 subunits within the villous core/stroma cells and not the trophoblast layer.
These findings support that both CS and PE affect nAChRs in the placenta, but that this is restricted to the villi.
•All 9 nAChR subunits are expressed in cells of the placenta villi and decidua.•Changes in nAChR were only in the villi of placentas from smokers and preeclampsia.•The β1 subunit was affected in smokers.•The β2 subunit was affected in preeclamptics.•The α9 subunit was affected in preeclamptic smokers.
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