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Abstract Background The formation of blood vessels within solid tumors directly contributes to cancer growth and metastasis. Until recently, tumor vasculature was thought to occur exclusively via endothelial cell (EC) lined structures (i.e. angiogenesis), but a second source of tumor vasculature arises from the cancer cells themselves, a process known as vasculogenic mimicry (VM). While it is generally understood that the function of VM vessels is the same as that of EC-lined vessels (i.e. to supply oxygen and nutrients to the proliferating cancer cells), the molecular mechanisms underpinning VM are yet to be fully elucidated. Methods Human VM-competent melanoma cell lines were examined for their VM potential using the in vitro angiogenesis assays (Matrigel), together with inhibition studies using small interfering RNA and blocking monoclonal antibodies. Invasion assays and adhesion assays were used to examine cancer cell function. Results Herein we demonstrate that CD36, a cell surface glycoprotein known to promote angiogenesis by ECs, also supports VM formation by human melanoma cancer cells. In silico analysis of CD36 expression within the melanoma cohort of The Cancer Genome Atlas suggests that melanoma patients with high expression of CD36 have a poorer clinical outcome. Using in vitro ‘angiogenesis’ assays and CD36-knockdown approaches, we reveal that CD36 supports VM formation by human melanoma cells as well as adhesion to, and invasion through, a cancer derived extracellular matrix substrate. Interestingly, thrombospondin-1 (TSP-1), a ligand for CD36 on ECs that inhibits angiogenesis, has no effect on VM formation. Further investigation revealed a role for laminin, but not collagen or fibronectin, as ligands for CD36 expressing melanoma cells. Conclusions Taken together, this study suggests that CD36 is a novel regulator of VM by melanoma cancer cells that is facilitated, at least in part, via integrin-α3 and laminin. Unlike angiogenesis, VM is not perturbed by the presence of TSP-1, thus providing new information on differences between these two processes of tumor vascularization which may be exploited to combat cancer progression.

In recent decades, male infertility has been correlated with the shortening of sperm telomeres. Telomeres regulate the reproductive lifespan by mediating the synapsis and homologous recombination of chromosomes during gametogenesis. They are composed of thousands of hexanucleotide DNA repeats (TTAGGG) that are coupled to specialized shelterin complex proteins and non-coding RNAs. Telomerase activity in male germ cells ensures that the telomere length is maintained at maximum levels during spermatogenesis, despite telomere shortening due to DNA replication or other genotoxic factors such as environmental pollutants. An emerging body of evidence has associated an exposure to pollutants with male infertility. Although telomeric DNA may be one of the important targets of environmental pollutants, only a few authors have considered it as a conventional parameter for sperm function. The aim of this review is to provide comprehensive and up-to-date data on the research carried out so far on the structure/function of telomeres in spermatogenesis and the influence of environmental pollutants on their functionality. The link between pollutant-induced oxidative stress and telomere length in germ cells is discussed.

The sterile alpha motif and leucine zipper containing kinase ZAK (AZK, MLT, MLK7), is a MAPK-kinase kinase (MKKK). Like most MAPKKKs which are known to activate the c-Jun. amino-terminal kinase (JNK) pathway, ZAK has been shown to participate in the transduction of Transforming growth factor-β (TGF-β)-mediated non-canonical signaling. A role for ZAK in SMAD-dependent, canonical TGF-β signaling has not been previously appreciated. Using a combination of functional genomics and biochemical techniques, we demonstrate that ZAK regulates canonical TGFβRI/II signaling in lung and breast cancer cell lines and may serve as a key node in the regulation of TGFBR kinase activity. Remarkably, we demonstrate that siRNA mediated depletion of ZAK strongly inhibited TGF-β dependent SMAD2/3 activation and subsequent promoter activation (SMAD binding element driven luciferase expression; SBE4-Luc). A ZAK specific inhibitor (DHP-2), dose-dependently activated the bioluminescent TGFBR-kinase activity reporter (BTR), blocked TGF-β induced SMAD2/3 phosphorylation and SBE4-Luc activation and cancer cell-invasion. In aggregate, these findings identify a novel role for the ZAK kinase in canonical TGF-β signaling and an invasive cancer cell phenotype thus providing a novel target for TGF-β inhibition.

Objectives The purpose of this study is to test the hypothesis that the link between socioeconomic status (SES) and resilience is mediated by reserve-building activities. Design Cross-sectional observational study. Structural equation modelling (SEM) was used to test the mediation hypothesis. Setting Web-based survey. Participants Participants with a chronic medical condition were recruited from Rare Patient Voice. Primary and secondary outcome measures DeltaQuest Reserve-Building Measure; demographic variables to capture SES; Centers for Disease Control Healthy Days Core Module; Self-Administered Comorbidity Questionnaire. Resilience was operationalised using residual modelling. Results The study sample included 442 patients (mean age 49, 85% female). SES was modelled as a bifactor model composed of general SES and specific factors for personal finance and parent's education. A series of simple mediation models predicting resilience led to the selection of three reserve-building activities for subsequent SEM-based mediation models: Active in the World, Outdoor and Exercise. The full SEM model supported the hypothesis that the relationships from both general SES and personal finance to resilience were mediated by engaging in the three reserve-building activities. In addition, the number of comorbidities partially mediated the relationship between personal finance and reserve-building. Those with more comorbidities generally had lower levels of resilience. Conclusions This study provides suggestive evidence that reserve-building activities may be one pathway by which SES is associated with resilience: people of higher SES are more likely to engage in reserve-building activities that are intellectually stimulating, involve Outdoor pursuits and include physical Exercise. These reserve-building activities are not costly to pursue. These findings may empower patients to introduce more such reserve-building activities into their lives. [ABSTRACT FROM AUTHOR]

Background Prehospital plasma administration during air medical transport reduces the endotheliopathy of trauma, circulating pro-inflammatory cytokines, and 30-day mortality among traumatically injured patients at risk of hemorrhagic shock. No clinical data currently exists evaluating the age of thawed plasma and its association with clinical outcomes and biomarker expression post-injury.Methods We performed a secondary analysis from the prehospital plasma administration randomized controlled trial, PAMPer. We dichotomized the age of thawed plasma creating three groups: standard-care, YOUNG (day 0–1) plasma, and OLD (day 2–5) plasma. We generated HRs and 95% CIs for mortality. Among all patients randomized to plasma, we compared predicted biomarker values at hospital admission (T0) and 24 hours later (T24) controlling for key difference between groups with a multivariable linear regression. Analyses were repeated in a severely injured subgroup.Results Two hundred and seventy-one patients were randomized to standard-care and 230 to plasma (40% YOUNG, 60% OLD). There were no clinically or statistically significant differences in demographics, injury, admission vital signs, or laboratory values including thromboelastography between YOUNG and OLD. Compared with standard-care, YOUNG (HR 0.66 (95% CI 0.41 to 1.07), p=0.09) and OLD (HR 0.64 (95% CI 0.42 to 0.96), p=0.03) plasma demonstrated reduced 30-day mortality. Among those randomized to plasma, plasma age did not affect mortality (HR 1.04 (95% CI 0.60 to 1.82), p=0.90) and/or adjusted serum markers by plasma age at T0 or T24 (p>0.05). However, among the severely injured subgroup, OLD plasma was significantly associated with increased adjusted inflammatory and decreased adjusted endothelial biomarkers at T0.Discussion Age of thawed plasma does not result in clinical outcome or biomarker expression differences in the overall PAMPer study cohort. There were biomarker expression differences in those patients with severe injury. Definitive investigation is needed to determine if the age of thawed plasma is associated with biomarker expression and outcome differences following traumatic injury.Level of evidence II.

Background Rib fractures are associated with significant morbidity and mortality in polytraumatized patients. There is considerable variability in the management (operative vs. non-operative) and timing of operative intervention. Although Eastern Association for the Surgery of Trauma (EAST) guidelines recommend early operative intervention in patients with flail chest, there are no strong recommendations regarding operative fixation in patients with a non-flail chest rib fracture pattern.Methods We reviewed our Trauma Quality Improvement Program database for patients aged 18 to 99 who underwent operative intervention of ribs from January 2016 to July 2019. We examined hospital length of stay (LOS), intensive care unit (ICU) LOS, ventilator days, Injury Severity Score, age, discharge disposition and packed red blood cell transfusions. Similarly, we collected data from patients aged 18 to 99 who had one or more rib fractures in this time frame. We compared results in a 4:1 ratio of patients managed non-operatively to patients managed operatively. The patient groups were matched based on age, number of rib fractures and presence of bilateral rib fractures.Results Between January 2016 and July 2019, 33 of 4189 total patients diagnosed with rib fractures underwent operative fixation; the matched non-operative group consisted of 132 patients. The statistically significant differences included presence of bilateral rib fractures, displaced rib fractures and flail chest segments. The median ICU days were longer in the operative group (6.0 vs. 3.5 days). A subgroup analysis of patients without flail segments demonstrated a significant presence of displaced rib fractures.Our single-institution matched comparison of outcomes in operative intervention versus Non-operative Management (NOM) of rib fractures found an increased median number of ICU days. Patients who underwent operative intervention often stayed in the ICU preoperatively and postoperatively for aggressive pulmonary hygiene and pain control, suggesting observer bias. The increased incidence of displaced rib fractures and the presence of a flail segment in the operative group demonstrate congruence with EAST guidelines. A subgroup analysis of patients without flail segment did not demonstrate differences in outcomes nor shoulder girdle injury characteristics.Level of evidence This article presents level III evidence that can be used by other clinicians to analyze eligibility for patients to undergo surgical stabilization of rib fracture (SSRF) and to provide counterarguments for performing SSRF in a heterogenous group of patients.

BACKGROUND: In Italy, a recent law has imposed a ban on the fertilization of more than three oocytes at one time, and all resulting embryos produced must be transferred simultaneously. The aim of the present controlled study was to assess the clinical feasibility and efficacy of the perifollicular vascularity assessment for oocyte selection in IVF cycles. METHODS: Fifty-four young primary infertile non-obese women (27 cases and 27 age- and BMI-matched controls) underwent IVF cycles. The choice of the oocytes to fertilize was performed according to perifollicular vascularization in the experimental group, whereas in the control group, the standard morphologic criteria alone were used. The dose of gonadotrophins used, the dominant follicles obtained, the duration of the ovarian stimulation, the number of oocytes retrieved, the number/quality of oocytes fertilized and of cleaved embryos, cycle cancellation, implantation, clinical pregnancy, ongoing pregnancy, multiple pregnancies and ovarian hyperstimulation syndrome rates were assessed in each group. RESULTS: The assessment of perifollicular vascularity was feasible in 88.9% of cases. No difference between groups was detected in any parameter evaluated. CONCLUSION: Power Doppler assessment of perifollicular vascularity seems to have no clinical utility for oocyte selection in IVF cycles for young infertile women. [ABSTRACT FROM AUTHOR]

BACKGROUND: There are few data in the literature regarding the utility of metfomin before and during gonadotrophin administration in women with polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of the pre-treatment and co-administration of metformin in infertile PCOS women treated with controlled ovarian stimulation (COS) followed by timed intercourse (TI) or intrauterine insemination (IUI). METHODS: Seventy insulin-resistant primary infertile women with PCOS were randomized to receive metformin cloridrate (850 mg twice daily; group A) or placebo tablets (two tablets daily; group B) for 3 months. Three trials of COS using highly purified urinary FSH (hpFSH) plus TI/IUI were performed. Number of ampoules of gonadotrophin used, duration of the ovarian stimulation, cycle cancellation, ovulation, pregnancy, abortion, live birth, mono-ovulatory cycles, multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) rates were assessed. RESULTS: No difference between groups was detected in ovulation, cycle cancellation, pregnancy, abortion, live birth, multiple pregnancies and OHSS rates. The mono-ovulatory cycle rates were significantly (P = 0.002) more frequent in group A than in group B, whereas the days of stimulation for non-cancelled cycles and the number of vials of gonadotrophins used were significantly (P < 0.001) higher in group A than in group B. CONCLUSION: In insulin-resistant women with PCOS, metformin pre-treatment and co-administration with hpFSH increases the mono-ovulatory cycles. [ABSTRACT FROM AUTHOR]

This study describes a steady-state sequence that uses a radial k-space trajectory and alternating echo times (TEs) between even and odd k-space views. The sequence generated a single data set that was used to reconstruct images with inherent fat suppression. This fat suppression results from the fat phase variation in alternate echoes giving rise to cancellation in the central portion of k-space. This new fat-suppression method provides inherent fat suppression in half the acquisition time relative to the radial two-point Dixon method. The improvement in k-space sampling efficiency is demonstrated in phantom and clinical images, and through measured point-spread functions (PSFs). As a result, the radial alternating TE sequence offers improved temporal resolution over a radial version of the two-point Dixon sequence by requiring fewer total projections to obtain the same effective resolution in water-based tissues. Magn Reson Med 50:1095–1099, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a less-invasive technique for aortic occlusion (AO). Commonly performed in the emergency department (ED), the role of intraoperative placement is less defined. We hypothesized that operating room (OR) placement is associated with increased in-hospital mortality.Methods The American Association for the Surgery of Trauma AORTA registry was used to identify patients undergoing REBOA. Injury characteristics and outcomes data were compared between OR and ED groups. The primary outcome was in-hospital mortality; secondary outcomes included total AO time, transfusion requirements, and acute kidney injury.Results Location and timing of catheter insertion were available for 305 of 321 (95%) subjects. 58 patients underwent REBOA in the OR (19%). There were no differences with respect to sex, admission lactate, and Injury Severity Score. The OR group was younger (33 years vs. 41 years, p=0.01) and with more penetrating injuries (36% vs. 15%, p

Objectives: This study aims to assess the correlation of CT-based structural rigidity analysis with mechanically determined axial rigidity in normal and metabolically diseased rat bone. Methods: A total of 30 rats were divided equally into normal, ovariectomized, and partially nephrectomized groups. Cortical and trabecular bone segments from each animal underwent micro-CT to assess their average and minimum axial rigidities using structural rigidity analysis. Following imaging, all specimens were subjected to uniaxial compression and assessment of mechanically-derived axial rigidity. Results: The average structural rigidity-based axial rigidity was well correlated with the average mechanically-derived axial rigidity results (R\(^2\) = 0.74). This correlation improved significantly (p < 0.0001) when the CT-based Structural Rigidity Analysis (CTRA) minimum axial rigidity was correlated to the mechanically-derived minimum axial rigidity results (R\(^2\) = 0.84). Tests of slopes in the mixed model regression analysis indicated a significantly steeper slope for the average axial rigidity compared with the minimum axial rigidity (p = 0.028) and a significant difference in the intercepts (p = 0.022). The CTRA average and minimum axial rigidities were correlated with the mechanically-derived average and minimum axial rigidities using paired t-test analysis (p = 0.37 and p = 0.18, respectively). Conclusions: In summary, the results of this study suggest that structural rigidity analysis of micro-CT data can be used to accurately and quantitatively measure the axial rigidity of bones with metabolic pathologies in an experimental rat model. It appears that minimum axial rigidity is a better model for measuring bone rigidity than average axial rigidity.

Background: Thoracic insufficiency syndrome represents a novel form of postnatal restrictive respiratory disease occurring in children with early-onset scoliosis and chest wall anomalies. Expansion thoracoplasty improves lung volumes in children with thoracic insufficiency syndrome; however, how it affects lung development is unknown. Questions/purposes: Using a rabbit model of thoracic insufficiency syndrome, we evaluated the effect of expansion thoracoplasty on the response of biologic mechanisms in the alveolar microstructure. Methods: Using archived material from a previous experiment, 10 4-week-old New Zealand rabbits were divided into three groups: normal (n = 3), disease (n = 3), and treated (n = 4). Left ribs four to eight were tethered in seven rabbits at age 5 weeks to induce hypoplasia of the left hemithorax (disease). At age 10 weeks, four of these rabbits were treated by expansion thoracoplasty (treated). At age 24 weeks, lungs were excised and processed. Alveolar density and parenchymal airspace were measured on histologic sections. Immunohistochemistry was performed for vascular endothelial growth factor receptor 2 (angiogenesis), KI-67 (cell proliferation), and RAM-11 (macrophages). Results: Alveolar walls were poorly perfused and airspace fraction was larger (emphysematous) in disease rabbits than normal or treated rabbits. Immunohistochemistry provided inconclusive evidence to support the concept that pulmonary hypoplasia is induced by thoracic insufficiency syndrome and controlled by expansion thoracoplasty. Conclusions: Treatment of thoracic insufficiency syndrome by expansion thoracoplasty may prevent emphysematous changes in the alveolar microstructure, thereby enhancing gas exchange.

Minimally invasive and non-destructive methods to quantify glycosaminoglycans (GAGs) in articular cartilage extracellular matrix are of significant interest for the biochemical analysis of cartilage and diagnosis and tracking of osteoarthritis in vivo. Here, we report the use of cationic iodinated contrast agents in comparison to conventional anionic contrast agents for the quantitative monitoring of GAG concentrations with peripheral quantitative computed tomography. Using an ex vivo bovine osteochondral plug model, the cationic contrast agents were evaluated for their ability to distribute into articular cartilage and generate a positive relationship with GAG content. The cationic agents resulted in much higher equilibrium X-ray attenuations in cartilage extracellular matrix (ECM) than anionic agents. Experiments with samples subjected to enzymatic GAG degradation demonstrated that the cationic agents were up to five times more sensitive (p = 0.0001) to changes in GAG content and had a 24% higher correlation (p = 0.002) compared to the anionic agent (R2 = 0.86, p < 0.0001 compared with R2 = 0.62, p = 0.004). The natural inhomogeneous distribution of GAGs in the ECM could clearly be identified in undegraded samples., Chemistry and Chemical Biology

Surgical treatments such as the Roux-en-Y gastric bypass operation result in the successful treatment of morbid obesity; however, this type of operation may cause long-term side effects due to the reduced absorption of nutrients. Here, we present data suggesting that this operation can result in secondary infertility in males. Six healthy, previously fertile male subjects presented in our centre for secondary infertility after a Roux-en-Y gastric bypass operation for morbid obesity. Reproductive function was assessed with a series of spermiograms, and by testicular biopsy. Secondary azoospermy with complete spermatogenic arrest was diagnosed. The results suggest that weight reduction surgery may cause reproductive dysfunction. [ABSTRACT FROM AUTHOR]