Metabolic fingerprinting by nuclear magnetic resonance of hepatocellular carcinoma cells during p53 reactivation-induced senescence.

Cellular senescence is characterized by stable cell cycle arrest. Senescent cells exhibit a senescence-associated secretory phenotype that can promote tumor progression. The aim of our study was to identify specific nuclear magnetic resonance (NMR) spectroscopy-based markers of cancer cell senescence. For metabolic studies, we employed murine liver carcinoma Harvey Rat Sarcoma Virus (H-Ras) cells, in which reactivation of p53 expression induces senescence. Senescent and nonsenescent cell extracts were subjected to high-resolution proton (1H)-NMR spectroscopy-based metabolomics, and dynamic metabolic changes during senescence were analyzed using a magnetic resonance spectroscopy (MRS)-compatible cell perfusion system. Additionally, the ability of intact senescent cells to degrade the extracellular matrix (ECM) was quantified in the cell perfusion system. Analysis of senescent H-Ras cell extracts revealed elevated sn-glycero-3-phosphocholine, myoinositol, taurine, and creatine levels, with decreases in glycine, o-phosphocholine, threonine, and valine. These metabolic findings were accompanied by a greater degradation index of the ECM in senescent H-Ras cells than in control H-Ras cells. MRS studies with the cell perfusion system revealed elevated creatine levels in senescent cells on Day 4, confirming the 1H-NMR results. These senescence-associated changes in metabolism and ECM degradation strongly impact growth and redox metabolism and reveal potential MRS signals for detecting senescent cancer cells in vivo.

Mpox Surveillance Based on Rash Characteristics - 13 Emergency Departments, United States, June-December 2023.

In 2022, a global mpox outbreak occurred, primarily affecting gay and bisexual men who have sex with men (GBMSM). To screen for mpox's reemergence and investigate potentially unsuspected cases among non-GBMSM, prospective surveillance of patients aged ≥3 months with an mpox-compatible rash (vesicular, pustular, ulcerated, or crusted) was conducted at 13 U.S. emergency departments (EDs) during June-December 2023. Demographic, historical, and illness characteristics were collected using questionnaires and electronic health records. Lesions were tested for monkeypox virus using polymerase chain reaction. Among 196 enrolled persons, the median age was 37.5 years (IQR = 21.0-53.5 years); 39 (19.9%) were aged <16 years, and 108 (55.1%) were male. Among all enrollees, 13 (6.6%) were GBMSM. Overall, approximately one half (46.4%) and one quarter (23.5%) of enrolled persons were non-Hispanic White and non-Hispanic Black or African American, respectively, and 38.8% reported Hispanic or Latino (Hispanic) ethnicity. Unstable housing was reported by 21 (10.7%) enrollees, and 24 (12.2%) lacked health insurance. The prevalence of mpox among ED patients evaluated for an mpox-compatible rash was 1.5% (95% CI = 0.3%-4.4%); all persons with a confirmed mpox diagnosis identified as GBMSM and reported being HIV-negative, not being vaccinated against mpox, and having engaged in sex with one or more partners met through smartphone dating applications. No cases were identified among women, children, or unhoused persons. Clinicians should remain vigilant for mpox and educate persons at risk for mpox about modifying behaviors that increase risk and the importance of receiving 2 appropriately spaced doses of JYNNEOS vaccine to prevent mpox.

Effect of the use of platelet concentrates on new bone formation in alveolar ridge preservation: a systematic review, meta-analysis, and trial sequential analysis.

OBJECTIVES: To investigate the histomorphometric changes occurring in alveolar ridge preservation (ARP) based on the use of different plasma concentrates (PCs) in randomized clinical trials (RCT). There is controversy whether the placement of PCs in ARP is effective in the formation of new bone. MATERIALS AND METHODS: A systematic review search was conducted in PubMed, Scopus, Web of Science, and Cochrane Database to answer the PICO question: In patients undergoing tooth extraction followed by ARP, do PCs alone in the post-extraction socket in comparison with spontaneous healing improve new vital bone formation percentage in histomorphometric analysis after more than 10 weeks? The risk of bias was assessed and a meta-analysis was conducted. RESULTS: Of 3809 results, 8 studies were considered suitable for inclusion. A total of 255 teeth were extracted in 250 patients. Regarding the PCs used, ARP was performed with platelet- and leukocyte-rich fibrin (L-PRF) in 120 sockets, and with pure platelet-rich plasma (P-PRP) in 31 sockets and 104 sockets were controlled. PCs improved new bone formation in ARP with respect to the spontaneous healing group (SMD = 1.77, 95%C.I. = 1.47-2.06, p-value < 000.1). There were no differences between the different PCs (L-PRF and P-PRP). CONCLUSION: The results of this meta-analysis support the efficacy of the use of PCs in new bone formation in ARP. With respect to the different types of PCs studied, no differences were observed. CLINICAL RELEVANCE: When planning implant surgery after tooth extraction, treatment with PCs should be considered for ARP. Any PC increases new bone formation compared to spontaneous healing.

Efficacy and safety of a bioadhesive gel containing propolis extract, nanovitamin C and nanovitamin E on desquamative gingivitis: a double-blind, randomized, clinical trial.

OBJECTIVES: To evaluate the efficacy of a gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to professional plaque removal on desquamative gingivitis (DG). MATERIALS AND METHODS: A randomized clinical trial was conducted on patients suffering DG due to mucocutaneous diseases. Patients received professional supragingival prophylaxis with oral hygiene instructions and were randomly assigned to use test or control gels as toothpaste and to apply it on DG lesions 3 times/day for 4 weeks. DG clinical score (DGCS), clinical periodontal variables, and visual analog scale (VAS) for pain and oral health impact profile (OHIP-14) were collected at baseline, 2 and 4 weeks. RESULTS: Twenty-two patients were randomly assigned to test (n = 11) or control group (n = 11). Eighteen had diagnosis of oral lichen planus and four of mucous membrane pemphigoid. DGCS statistically decreased in both groups after treatment with no significant differences between groups. Clinical periodontal outcomes decreased in both groups, but no significant differences were observed. Periodontal variables statistically improved only in test group after treatment. VAS and OHIP-14 scores decreased in test and control groups without significant differences. However, only one test group showed a statistically significant decrease in VAS and OHIP-14 scores after treatment. No adverse effects were reported. CONCLUSIONS: Test gel may alleviate DG and improve quality of life without side effects. CLINICAL RELEVANCE: A gel-containing propolis extract, nanovitamin C, and nanovitamin E as adjuvants to mechanical debridement may improve both clinical and patient related outcomes in DG patients without side effects. CLINICAL TRIAL REGISTRATION: The study protocol was registered at clinicaltrials.gov with the following number: NCT05124366 on October 16, 2021.

Fast and Reliable Sending of Generic Object Oriented Substation Event Frames between Remote Locations over Loss-Prone Networks.

WAMPAC (Wide Area Monitoring Protection and Control) applications are becoming crucial for granting a stable operation of the electricity transmission grid. These systems use a set of sensors distributed between different electrical substations to gather real-time measurements from the field. These sensors are called Phasor Measurement Units (PMUs). Using the gathered data, different monitoring, protection, and control algorithms are run in a Phasor Data Concentrator (PDC) located in a central location. These algorithms close the loop via the generation of remedial commands, which are sent back to the field level with stringent delay, security, and reliability requirements. GOOSE (Generic Object Oriented Substation Events) protocol, defined by IEC 61850 (IEC stands for International Electrotechnical Commission), is used for that aim and also considers the option of sending these commands over IP networks (this option is called Routed-GOOSE). The present article proposes two alternatives for the tunneling of GOOSE frames over IP. Both options allow the decoupling of the transmission and the security aspects, thus increasing flexibility and allowing for easier deployment. The first option, called VX-GOOSE, is a combination of standard protocols, allowing the sending of these frames over UDP/IP tunnels. The tests that have been carried out demonstrate that, under certain network conditions, the transmission of GOOSE frames over UDP may fail, and in some extreme cases, even a whole burst of GOOSEs could be lost. This may have very bad consequences for a distributed electrical system. It should be noted that this limitation affects both VX-GOOSE and Routed-GOOSE. To overcome these limitations, the second option, called Simplemux blast mode, includes a novel mechanism that provides delivery guarantees and a reduced delay, with the counterpart of a certain degree of redundancy. As shown in the experiments, the incurred delays can be significantly reduced when remote locations are connected via unreliable networks, whereas the bandwidth increase caused by redundancy can be kept at reasonable levels. Finally, it should be remarked that although GOOSE is a relevant example use case, this approach can be applied in other fields where flows require very low delay and delivery guarantees.

mRNA Levels of Aromatase, 5α-Reductase Isozymes, and Prostate Cancer-Related Genes in Plucked Hair from Young Men with Androgenic Alopecia.

Androgenic alopecia (AGA) is the most prevalent type of progressive hair loss and has psychological repercussions. Nevertheless, the effectiveness of current pharmacological treatments remains limited, in part because the molecular basis of the disease has not been fully elucidated. Our group previously highlighted the important roles of aromatase and 5α-reductase (5α-R) in alopecia in young women with female pattern hair loss. Additionally, an association has been proposed between AGA and prostate cancer (PCa), suggesting that genes implicated in PCa would also be involved in AGA. A low-invasive, sensitive, and precise method was used to determine mRNA levels of aromatase, 5α-R isozymes, and 84 PCa-related genes in samples of plucked hair from young men with AGA and controls. Samples were obtained with a trichogram from the vertex scalp, and mRNA levels were quantified using real-time RT-PCR. The men with AGA had significantly higher 5α-R2 mRNA levels in comparison to controls; interestingly, some of them also showed markedly elevated mRNA levels of 5α-R1 or 5α-R3 or of both, which may explain the varied response to 5α-R inhibitor treatments. The men with AGA also showed significant changes versus controls in 6 out of the 84 genes implicated in PCa. This study contributes greater knowledge of the molecular bases of AGA, facilitating early selection of the most appropriate pharmacological therapy and opening the way to novel treatments.

Impact of chronic exposure of rats to bisphenol A from perinatal period to adulthood on intraprostatic levels of 5α-reductase isozymes, aromatase, and genes implicated in prostate cancer development.

The synergetic effect of estrogens and androgens is known to play a crucial role in the physiopathology of the prostate gland. Bisphenol A (BPA) is an endocrine disrupting compound that can interfere with endocrine hormone functioning and thereby influence prostate development. The objective of this study was to examine the impact on prostate expression of aromatase, 5α-R isozymes, and prostate cancer-related genes of exposure to low doses of BPA from perinatal period to adulthood. Vehicle or BPA (2.5 µg/kg b.w./day) was administered to gestating Wistar rats from gestational day 12 (GD12) to parturition and then to their male pups from postnatal day 1 (PND1) until euthanization on PND90. Their prostate glands were examined by qRT-PCR, Western blot, PCR array, and morphological study. mRNA and protein levels of 5α-R2 were significantly reduced and mRNA and protein levels of aromatase were significantly increased in BPA-treated animals, which also showed modifications of 8 out of the 84 key genes implicated in the development of prostate cancer. Because BPA interferes with genes involved in intraprostatic androgen and estrogen production and others implicated in prostate cancer, research is warranted into the prostate disease risk associated with chronic low-dose BPA exposure throughout life.

Salivary LDH in oral cancer and potentially malignant disorders: A systematic review and meta-analysis.

OBJECTIVES: To evaluate whether salivary lactate dehydrogenase (LDH) levels are increased in patients with oral cancer (OC) or oral potentially malignant disorders (OPMD) when compared to a healthy control group (CG). MATERIAL AND METHODS: We conducted a comprehensive search of specialized databases (PubMed/MEDLINE, The Cochrane Library, Web of Science, Scopus, and OpenGrey), including observational analytical studies evaluating the salivary LDH levels (in UI/L or µ/L) in OC or OPMD patients and compared them with a CG. RESULTS: Thirteen case-control studies were included. A total of 755 patients were evaluated, including 303 OC cases, 149 OPMD cases, and 303 controls. The meta-analysis showed that LDH levels were higher within the OC group than the CG (SMD 9.49; 95% CI 6.97-12; p = .00001). Patients with oral leucoplakia (SMD 11.67; 95% CI 1.01-22.33; p = .03) and oral submucous fibrosis (SMD 25.83; 95% CI -1.74-53.40; p = .07) also presented higher levels than the CG. In addition, OC patients had higher salivary LDH levels than oral leucoplakia patients (SMD 5.62; 95% CI 2.14-9.11; p = .002). Heterogeneity was high across all the evaluated studies. CONCLUSIONS: The determination of salivary LDH may be a useful method for screening and tracking OC and OPMD, but new protocolized studies are required to establish precise cutoff values.

Transport-driven engineering of liposomes for delivery of α-particle radiotherapy to solid tumors: effect on inhibition of tumor progression and onset delay of spontaneous metastases.

PURPOSE: Highly cytotoxic α-particle radiotherapy delivered by tumor-selective nanocarriers is evaluated on metastatic Triple Negative Breast Cancer (TNBC). On vascularized tumors, the limited penetration of nanocarriers (<50-80 µm) combined with the short range of α-particles (40-100 µm) may, however, result in only partial tumor irradiation, compromising efficacy. Utilizing the α-particle emitter Actinium-225 (225Ac), we studied how the therapeutic potential of a general delivery strategy using nanometer-sized engineered liposomes was affected by two key transport-driven properties: (1) the release from liposomes, when in the tumor interstitium, of the highly diffusing 225Ac-DOTA that improves the uniformity of tumor irradiation by α-particles and (2) the adhesion of liposomes on the tumors' ECM that increases liposomes' time-integrated concentrations within tumors and, therefore, the tumor-delivered radioactivities. METHODS: On an orthotopic MDA-MB-231 TNBC murine model forming spontaneous metastases, we evaluated the maximum tolerated dose (MTD), biodistributions, and control of tumor growth and/or spreading after administration of 225Ac-DOTA-encapsulating liposomes, with different combinations of the two transport-driven properties. RESULTS: At 83% of MTD, 225Ac-DOTA-encapsulating liposomes with both properties (1) eliminated formation of spontaneous metastases and (2) best inhibited the progression of orthotopic xenografts, compared to liposomes lacking one or both properties. These findings were primarily affected by the extent of uniformity of the intratumoral microdistributions of 225Ac followed by the overall tumor uptake of radioactivity. At the MTD, long-term toxicities were not detected 9.5 months post administration. CONCLUSION: Our findings demonstrate the potential of a general, transport-driven strategy enabling more uniform and prolonged solid tumor irradiation by α-particles without cell-specific targeting.

The Rapid Evaluation of COVID-19 Vaccination in Emergency Departments for Underserved Patients Study.

STUDY OBJECTIVE: Emergency departments (EDs) often serve vulnerable populations who may lack primary care and have suffered disproportionate COVID-19 pandemic effects. Comparing patients having and lacking a regular source of medical care and other ED patient characteristics, we assessed COVID-19 vaccine hesitancy, reasons for not wanting the vaccine, perceived access to vaccine sites, and willingness to get the vaccine as part of ED care. METHODS: This was a cross-sectional survey conducted from December 10, 2020, to March 7, 2021, at 15 safety net US EDs. Primary outcomes were COVID-19 vaccine hesitancy, reasons for vaccine hesitancy, and sites (including EDs) for potential COVID-19 vaccine receipt. RESULTS: Of 2,575 patients approached, 2,301 (89.4%) participated. Of the 18.4% of respondents who lacked a regular source of medical care, 65% used the ED as their usual source of health care. The overall rate of vaccine hesitancy was 39%; the range among the 15 sites was 28% to 58%. Respondents who lacked a regular source of medical care were more commonly vaccine hesitant than those who had a regular source of medical care (47% versus 38%, 9% difference, 95% confidence interval 4% to 14%). Other characteristics associated with greater vaccine hesitancy were younger age, female sex, Black race, Latinx ethnicity, and not having received an influenza vaccine in the past 5 years. Of the 61% who would accept a COVID-19 vaccine, 21% stated that they lacked a primary physician or clinic at which to receive it; the vast majority (95%) of these respondents would accept the COVID-19 vaccine as part of their care in the ED. CONCLUSION: ED patients who lack a regular source of medical care are particularly hesitant regarding COVID-19 vaccination. Most COVID-19 vaccine acceptors would accept it as part of their care in the ED. EDs may play pivotal roles in COVID-19 vaccine messaging and delivery to highly vulnerable populations.

Short-term efficacy of a gel containing propolis extract, nanovitamin C and nanovitamin E on peri-implant mucositis: A double-blind, randomized, clinical trial.

OBJECTIVE: To determine the efficacy of a gel containing propolis extract, nanovitamin C and nanovitamin E as adjuvant to mechanical debridement in the treatment of peri-implant mucositis (PM). BACKGROUND: Propolis has anti-inflammatory and antibacterial effect that may improve peri-implant health. METHODS: A randomized, double-blind study was performed on patients with at least one implant with PM. Participants received a professional prophylaxis and were instructed to use either test or a control gel as toothpaste three times/day for 1 month. Clinical and microbiological parameters were evaluated. PM resolution was considered in absence of bleeding on probing (BOP). Data were analysed with Mann-Whitney U, Wilcoxon signed-rank and chi-square tests. RESULTS: Forty-six patients participated (23 in each group). After treatment, 26.1% of test patients showed complete PM resolution versus 0% in control group (p = .02). Significant reductions were observed in plaque index (p = .03), BOP (p = .04) and probing depths (p = .027) in test compared with control group. The reduction in Tannerella forsythia was statistically greater in test than in control group at 1-month follow-up (p = .02). Porphyromonas gingivalis was statistically reduced in test group from baseline to 1-month follow-up (p = .05). CONCLUSION: Test gel clinically improved PM and showed certain antimicrobial effect after 1 month in comparison with control group. Further long-term clinical trials are required to confirm these results.

Differences in platelet-rich plasma composition influence bone healing.

AIM: Platelet-rich plasma (PRP) is an autologous blood-derived material that has been used to enhance bone regeneration. Clinical studies, however, reported inconsistent outcomes. This study aimed to assess the effect of changes in leucocyte and PRP (L-PRP) composition on bone defect healing. MATERIALS AND METHODS: L-PRPs were prepared using different centrifugation methods and their regenerative potential was assessed in an in-vivo rat model. Bilateral critical-size tibial bone defects were created and filled with single-spin L-PRP, double-spin L-PRP, or filtered L-PRP. Empty defects and defects treated with collagen scaffolds served as controls. Rats were euthanized after 2 weeks, and their tibias were collected and analysed using micro-CT and histology. RESULTS: Double-spin L-PRP contained higher concentrations of platelets than single-spin L-PRP and filtered L-PRP. Filtration of single-spin L-PRP resulted in lower concentrations of minerals and metabolites. In vivo, double-spin L-PRP improved bone healing by significantly reducing the size of bone defects (1.08 ± 0.2 mm3 ) compared to single-spin L-PRP (1.42 ± 0.27 mm3 ) or filtered L-PRP (1.38 ± 0.28 mm3 ). There were fewer mast cells, lymphocytes, and macrophages in defects treated with double-spin L-PRP than in those treated with single-spin or filtered L-PRP. CONCLUSION: The preparation method of L-PRP affects their composition and potential to regenerate bone.

Application to visualize simultaneous vibrations of plates and ribs in a violin.

A code was written to explore, in real-time, experimental operational deflection shapes up to 5 kHz of a violin soundbox. The animations can be rotated and zoomed using the mouse, while the developed graphical user interface (GUI) allows controlling the frequency, amplitude, and frame-per-second rate. Also, some parts of the model can be hidden to improve the visualization of specific details of interest. The measurements-performed by students as laboratory exercise-include the ribs and not only the plates as it is traditionally done, thus the vibrations of the soundbox can be analyzed as a whole. Since the GUI was developed under a cross-platform open-source software (scilab), it can be easily installed and used as an educational tool for traditional in-person learning or online learning.

Molecular and functional imaging insights into the role of hypoxia in cancer aggression.

Hypoxia in cancers has evoked significant interest since 1955 when Thomlinson and Gray postulated the presence of hypoxia in human lung cancers, based on the observation of necrosis occurring at the diffusion limit of oxygen from the nearest blood vessel, and identified the implication of these observations for radiation therapy. Coupled with discoveries in 1953 by Gray and others that anoxic cells were resistant to radiation damage, these observations have led to an entire field of research focused on exploiting oxygenation and hypoxia to improve the outcome of radiation therapy. Almost 65 years later, tumor heterogeneity of nearly every parameter measured including tumor oxygenation, and the dynamic landscape of cancers and their microenvironments are clearly evident, providing a strong rationale for cancer personalized medicine. Since hypoxia is a major cause of extracellular acidosis in tumors, here, we have focused on the applications of imaging to understand the effects of hypoxia in tumors and to target hypoxia in theranostic strategies. Molecular and functional imaging have critically important roles to play in personalized medicine through the detection of hypoxia, both spatially and temporally, and by providing new understanding of the role of hypoxia in cancer aggressiveness. With the discovery of the hypoxia-inducible factor (HIF), the intervening years have also seen significant progress in understanding the transcriptional regulation of hypoxia-induced genes. These advances have provided the ability to silence HIF and understand the associated molecular and functional consequences to expand our understanding of hypoxia and its role in cancer aggressiveness. Most recently, the development of hypoxia-based theranostic strategies that combine detection and therapy are further establishing imaging-based treatment strategies for precision medicine of cancer.

Exploring design variations of the Titian Stradivari violin using a finite element model.

Because violins are traditionally hand-crafted using wood, each one is unique. This makes the design of repeatable experiments studying some aspects of its dynamic behavior unfeasible. To tackle this problem, an adjustable finite element (FE) model of a violin soundbox using the geometry and behavior of the "Titian" Stradivari was developed in this paper. The model is parametric, so its design and material properties can be varied for before/after comparisons in both the frequency and time domains. Systematic simulations revealed that f-holes set lower in the top, as seen in some Stradivari violins (e.g., Hellier, Cremonese), raise the frequency of the Hill (a feature in the bridge mobility); conversely, the higher set f-holes seen in some Guarneri violins (e.g., Principe Doria) reduces such frequency. This agrees with the widespread belief that the high-frequency response of Stradivari violins is stronger than Guarneri violins. Changes in the response of the system were quantified once each part of the design was added, calling attention to the influence of the blocks on the behavior of signature modes, especially in the frequency and shape of B1 +. A text file of the FE model is available in supplemental materials; it runs in ANSYS (free version), for which guides are included.

MRI and MRS of intact perfused cancer cell metabolism, invasion, and stromal cell interactions.

Because of the spatial and temporal heterogeneities of cancers, technologies to investigate cancer cells and the consequences of their interactions with abnormal physiological environments, such as hypoxia and acidic extracellular pH, with stromal cells, and with the extracellular matrix, under controlled conditions, are valuable to gain insights into the functioning of cancers. These insights can lead to an understanding of why cancers invade and metastasize, and identify effective treatment strategies. Here we have provided an overview of the applications of MRI/MRS/MRSI to investigate intact perfused cancer cells, their metabolism and invasion, and their interactions with stromal cells and the extracellular matrix.

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001.

Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo.

BACKGROUND: Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. METHODS: We used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours. RESULTS: CAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space. CONCLUSIONS: CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.

Platelet concentrates for bone regeneration: Current evidence and future challenges.

Activated platelet concentrates are autologous blood preparations containing supraphysiological concentration of platelets. Platelet concentrates are commonly used for bone regeneration purposes based on the fact that growth factors released from activated platelets alpha granules have osteoinductive effects on bone cells. Although most preclinical and clinical studies show that platelet concentrates improve the outcomes of bone regeneration procedures, some studies reported conflicting results and even negative effects on bone healing. Several confounding parameters have been suggested as possible reasons for such inconsistencies (i.e. preparation and activation methods). However, heterogeneity in clinical studies makes drawing evidence-based conclusions difficult. On the other hand, recent findings show that the constituents of platelets dense granules (i.e. serotonin, ATP, Ca2+) have potential inhibitory effects on bone metabolism. Accordingly, we suggest that a partial explanation for the conflicting results could be the potential negative effects that dense granules may have on bone healing.

Implant treatment in pharmacologically immunosuppressed liver transplant patients: A prospective-controlled study.

OBJECTIVES: The main objective of this prospective study was to evaluate the long-term outcome of implant therapy in liver transplant patients (LTP). The secondary goal was to assess several implant- and patient-dependent variables, such as peri-implantitis (PI), peri-implant mucositis (PIM), bone loss (BL), and immediate postoperative complications. MATERIAL AND METHODS: Two groups, including 16 pharmacologically immunosuppressed LTP and 16 matched controls, received 52 and 54 implants, respectively, between 1999 and 2008. After evaluating the postoperative healing, a mean follow-up of more than 8 years was carried out, and radiographic, clinical, and periodontal parameters were recorded to evaluate implant survival and implant- and patient-dependent outcomes. RESULTS: The early postsurgical complications were similar in both groups. Implant survival rate was 100% in the LTP group and 98.15% in the CG. PIM was diagnosed in 35.42% of the implants and 64.29% of the patients of LTP group (LTPG) and in 43.40% of the implants and 56.25% of the patients in the CG. PI was detected in 4.17% of the implants and 7.10% of the patients in the LTPG and in 9.43% of the implants and 18.80% of the patients in the CG. CONCLUSION: Pharmacologically immunosuppression in liver transplant patients was not a risk factor for implant failure, nor for the incidence of peri-implant diseases. Liver transplant is not a contraindication for dental implant treatment, although these patients should be carefully monitored during follow-up care.