XFVM modelling of fracture aperture induced by shear and tensile opening.

In reservoir simulation, it is important to understand the mechanical behaviour of fractured rocks and the effect of shear and tensile displacements of fractures on their aperture. Tensile opening directly enhances the fracture aperture, whereas shear of a preexisting rough-walled fracture creates aperture changes dependent on the local stress state. Since fracture dilatation increases reservoir permeability, both processes must be included in a realistic and consistent manner into the mechanical reservoir simulation model. Here, we use the extended finite volume method (XFVM) to conduct flow and geomechanics simulations. In XFVM, fractures are embedded in a poroelastic matrix and are modelled with discontinuous basis functions. On each fracture segment the tractions and compressive forces are calculated, and one extra degree of freedom is added for both the shear and tensile displacement. In this particular XFVM implementation we assume that linear elasticity and steady state fluid pressure adequately constrain the effective stress. In this paper, shear dilation is not calculated a posteriori, but it enters the equations such that aperture changes directly affect the stress state. This is accomplished by adding shear dilation to the displacement gradients and therefore ascertains a consistent representation in the stress-strain relations and force balances. We illustrate and discuss the influence of this extra term in two simple test cases and in a realistic layer-restricted two-dimensional fracture network subjected to plausible in situ stress and pore pressure conditions.

Exploring the One Health Paradigm in Male Breast Cancer.

How cancer patterns in humans compare to those of other species remains largely unknown and there is an even bigger knowledge gap for rare cancers like male breast cancer. One Health is a convergence of human and animal healthcare that encourages cross-pollination of medical research uniting human and veterinary medicine. Recognising that breast cancer occurs spontaneously in other male species (e.g. primates, canines, felines), and knowing that no laboratory models exist for male breast cancer, which limits our ability to perform functional studies, we explored the feasibility of applying One Health to breast cancer in men by conducting a narrative review of the topic. Spontaneous development of breast cancer was reported in captive male primates and in companion canines and felines. Some parallels in tumour biology of human male breast cancer with canines and primates were found. The age distribution, pattern of biomarker expression and metastasis were similar, with mammary tumours typically detected after two-thirds of average lifespan. However, instances of triple negative and inflammatory breast cancer, which are rarely observed in human male breast cancer, were found in canines and histological classification was inconsistent between species. These disparities need redressing to enable full exploration of the One Health paradigm in rare cancers.

Paradoxical activation of oncogenic signaling as a cancer treatment strategy.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

HER2-Low Expression in Male Breast Cancer: Results from a Multicenter Series in Italy.

In the field of breast cancer care, a significant breakthrough has occurred with the recognition of HER2-low expression as a target for novel anti-HER2 antibody-drug conjugates (ADC). This discovery is reshaping the treatment landscape, challenging previous perceptions that considered HER2-low as clinically insignificant. The ability to target HER2-low expression is expected to have substantial clinical implications, irrespective of gender, including in cases of male breast cancer (MBC). However, an estimate of the prevalence of the HER2-low subtype in MBC is missing. This retrospective, observational, multicenter study was aimed at characterizing the HER2-low subtype in MBC. For the purpose of this study, the three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) was used to reclassify the HER2-negative group into HER-0 or HER2-low subtypes. In the whole series of 144 invasive MBCs, 79 (54.9%) were HER2-0 (IHC scores of 0), 39 (27.1%) HER2-low (IHC scores of 1+/2+ with negative ISH), and 26 (18.0%) HER2-positive (IHC scores of 3+/2+ with positive ISH). Specifically, among hormone receptor-positive (HR+) HER2-negative invasive MBCs, 34.8% were HER2-low and 65.2% HER2-0. Compared with HER2-0, HER2-low subtype was associated with a positive lymph node involvement (p = 0.01). Other pathologic characteristics including histology, staging, and grading did not show notable variations between the two subtypes. The presence of germline BRCA1/2 pathogenic variants (PVs) did not significantly differ between HER2-0 and HER2-low MBCs. However, about 13% of HER2-low MBCs had germline PVs in BRCA1/2 genes, mainly BRCA2, a clinically relevant observation in the context of combined target therapy. Overall, our data, which focused on the largest gender-specific breast cancer series, to our knowledge, confirm that the emerging three-tiered categorization of HER2 (HER2-0, HER2-low, and HER2-positive) can also be considered in MBC, to mitigate both the gender gap and the underrepresentation of males in clinical trials.

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond.

Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.

Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study.

BACKGROUND: Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients. METHODS: We performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel. RESULTS: PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88-6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17-45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12-20.56; p = 0.035). CONCLUSIONS: This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis.

Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies; however, this remains challenging due to a lack of broadly acting senolytic drugs. Using CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify loss of the death receptor inhibitor cFLIP as a common vulnerability of senescent cancer cells. Senescent cells are primed for apoptotic death by NF-κB-mediated upregulation of death receptor 5 (DR5) and its ligand TRAIL, but are protected from death by increased cFLIP expression. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of a variety of senescent cancer cells. Moreover, senescent cells sensitize adjacent non-senescent cells to killing by DR5 agonist through a bystander effect mediated by secretion of cytokines. We validate this 'one-two punch' cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity.

Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.

Color stability and microhardness alteration of irradiated dental enamel treated with a high fluoride concentration toothpaste.

OBJECTIVES: Radiotherapy (RT) is a kind of head and neck cancer (HNC) treatment, which is associated to the habit of smoking and can develop collateral effects in the oral cavity, such as the increase of caries prevalence. This study evaluated the color alteration, the microhardness, and the remineralizing potential of high fluoride concentration toothpastes on irradiated teeth. MATERIALS AND METHODS: Forty bovine teeth were used (6 × 6 × 2 mm) and after color (EasyShade, VITA) and microhardness initial readings were separated into two groups: exposed to cigarette smoke and non-exposed. All samples were submitted to RT (30 Gy) and to cariogenic challenge. New color and microhardness readings were done. After RT (60 Gy), the samples were submitted to simulated toothbrushing (73,000 cycles = 5 years of brushing) with two different toothpastes: conventional (1450 ppm) and high fluoride concentration (5000 ppm). Final color and microhardness readings were done after brushing. Data were analyzed with 2-way ANOVA with repeated measures and Tukey's test (p < .05). RESULTS: There was no color difference after RT, nor after brushing (p > .05). However, after brushing, microhardness values increased for the samples treated with high fluoride concentration toothpaste (p < .05). CONCLUSION: Radiotherapy did not influence the teeth color, and the high fluoride concentration toothpaste presented remineralizing potential; therefore, it could be used on the caries prevention related to HNC radiation. CLINICAL RELEVANCE: Considering its remineralizing potential, toothpastes with high fluoride concentration could be a proper alternative for caries prevention in patients undergoing radiotherapy.

Genetic and compound screens uncover factors modulating cancer cell response to indisulam.

Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15 Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.

Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology.

Introduction: Compared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). Methods: In this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples. Results and discussion: A total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy.

The Cancer SENESCopedia: A delineation of cancer cell senescence.

Cellular senescence is characterized as a stable proliferation arrest that can be triggered by multiple stresses. Most knowledge about senescent cells is obtained from studies in primary cells. However, senescence features may be different in cancer cells, since the pathways that are involved in senescence induction are often deregulated in cancer. We report here a comprehensive analysis of the transcriptome and senolytic responses in a panel of 13 cancer cell lines rendered senescent by two distinct compounds. We show that in cancer cells, the response to senolytic agents and the composition of the senescence-associated secretory phenotype are more influenced by the cell of origin than by the senescence trigger. Using machine learning, we establish the SENCAN gene expression classifier for the detection of senescence in cancer cell samples. The expression profiles and senescence classifier are available as an interactive online Cancer SENESCopedia.

Identification of Autophagy-Related Genes as Targets for Senescence Induction Using a Customizable CRISPR-Based Suicide Switch Screen.

Pro-senescence therapies are increasingly being considered for the treatment of cancer. Identifying additional targets to induce senescence in cancer cells could further enable such therapies. However, screening for targets whose suppression induces senescence on a genome-wide scale is challenging, as senescent cells become growth arrested, and senescence-associated features can take 1 to 2 weeks to develop. For a screen with a whole-genome CRISPR library, this would result in billions of undesirable proliferating cells by the time the senescent features emerge in the growth arrested cells. Here, we present a suicide switch system that allows genome-wide CRISPR screening in growth-arrested subpopulations by eliminating the proliferating cells during the screen through activation of a suicide switch in proliferating cells. Using this system, we identify in a genome-scale CRISPR screen several autophagy-related proteins as targets for senescence induction. We show that inhibiting macroautophagy with a small molecule ULK1 inhibitor can induce senescence in cancer cell lines of different origin. Finally, we show that combining ULK1 inhibition with the senolytic drug ABT-263 leads to apoptosis in a panel of cancer cell lines. IMPLICATIONS: Our suicide switch approach allows for genome-scale identification of pro-senescence targets, and can be adapted to simplify other screens depending on the nature of the promoter used to drive the switch.

The severity of microstrokes depends on local vascular topology and baseline perfusion.

Cortical microinfarcts are linked to pathologies like cerebral amyloid angiopathy and dementia. Despite their relevance for disease progression, microinfarcts often remain undetected and the smallest scale of blood flow disturbance has not yet been identified. We employed blood flow simulations in realistic microvascular networks from the mouse cortex to quantify the impact of single-capillary occlusions. Our simulations reveal that the severity of a microstroke is strongly affected by the local vascular topology and the baseline flow rate in the occluded capillary. The largest changes in perfusion are observed in capillaries with two inflows and two outflows. This specific topological configuration only occurs with a frequency of 8%. The majority of capillaries have one inflow and one outflow and is likely designed to efficiently supply oxygen and nutrients. Taken together, microstrokes bear potential to induce a cascade of local disturbances in the surrounding tissue, which might accumulate and impair energy supply locally.

A blockage in one of the tiny blood vessels or capillaries of the brain causes a 'microstroke'. Microstrokes do not cause the same level of damage as a major stroke, which is caused by a blockage in a larger blood vessel that completely cuts off oxygen to a part of the brain for a period. But microstrokes do increase the risk of developing conditions like dementia ­ including Alzheimer's disease ­ later in life. People with these neurodegenerative conditions have fewer capillaries in their brains. The capillaries make up a mesh-like network of millions of vessels that supply most of the energy and oxygen to the brain. Repeated microstrokes may contribute to progressive loss of capillaries over time. Reduced numbers of capillaries may increase memory loss and other brain difficulties. To better understand how microstrokes affect blood flow in the brain, Schmid et al. created a computer model to simulate blood flow in capillaries in the mouse brain. Then, they modeled what happens to the blood flow when one capillary is blocked. The experiments showed that the configuration of the blocked capillary determines how much blood flow in neighboring capillaries changes. Blockages in capillaries with two vessels feeding in and two vessels feeding out caused the greatest blood flow disturbances. But these 2-in-2-out vessels only make up about 8% of all brain capillaries. Blockages in capillaries with different configurations with respect to feeding vessels had less effect. The experiments suggest that most microstrokes have limited effects on blood flow on the scale of the entire brain because of redundancies in the capillary network in the brain. However, the ability of the capillary network to adapt and reroute blood flow in response to small blockages may decrease with aging. Over time, ministrokes in a single capillary may set off a chain reaction of disturbed blood flow and more blockages. This may decrease energy and oxygen supplies explaining age- and disease-related brain decline. Better understanding the effects of microstrokes on blood flow may help scientists develop new ways to prevent such declines.

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells.

Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.

A Novel Platform to Test In Vivo Single Gene Dependencies in t(8,21) and t(15,17) AML Confirms Zeb2 as Leukemia Target.

The increased usage of high-throughput technologies in cancer research, including genetic and drug screens, generates large sets of candidate targets that need to be functionally validated for their roles in tumor development. Thus, reliable and robust in vivo model systems are needed to perform reverse genetic experiments. Ideally, these models should allow for a conditional silencing of the target and an unambiguous identification of engineered cancer cells. Here, we present a platform consisting of: (i) t(8;21) and t(15;17) driven acute myeloid leukemia (AML) transgenic mice with constitutive expression of green fluorescent protein (GFP) and inducible expression of Cre recombinase, and (ii) REX, a modified pSico lentiviral vector for inducible shRNA expression and red fluorescent protein (RFP) as a selection marker. In this system, leukemic cells from transgenic mice are transduced with REX, flow sorted, and transplanted into syngeneic hosts. Gene interference is induced in established tumors by tamoxifen treatment. Dual-color cell fluorescence guides the in vivo identification of shRNA interfered AML cells, monitoring engraftment and disease progression. We tested the platform by inducing knockdown of Zeb2, a gene upregulated by AML1-ETO and PML-RARα oncogenes in pre-leukemic hematopoietic stem cell compartment, and observed a significant delay in leukemia onset. This proves the power and utility of the platform and confirms Zeb2 contribution to the pathogenesis of AML.

Impact of Sarcopenia on Simultaneous Pancreas and Kidney Transplantation Outcomes: A Retrospective Observational Cohort Study.

BACKGROUND: Sarcopenia has been identified as a predictive variable for surgical outcomes. We hypothesized that sarcopenia could be a key measure to identify frail patients and potentially predict poorer outcomes among recipients of simultaneous pancreas and kidney (SPK) transplants. METHODS: We estimated sarcopenia by measuring psoas muscle mass index (PMI). PMI was assessed on perioperative computed tomography (CT) scans of SPK recipients. RESULTS: Of the 141 patients identified between 2010 and 2018, 107 had a CT scan available and were included in the study. The median follow-up was 4 years (range, 0.5-9.1 y). Twenty-three patients had a low PMI, and 84 patients had a normal PMI. Patient characteristics were similar between the 2 groups except for body mass index, which was significantly lower in low PMI group (P < 0.001). Patient and kidney graft survival were not statistically different between groups (P = 0.851 and P = 0.357, respectively). A multivariate Cox regression analysis showed that patients with a low PMI were 6 times more likely to lose their pancreas allograft (hazard ratios, 5.4; 95% confidence intervals, 1.4-20.8; P = 0.015). Three out of 6 patients lost their pancreas graft due to rejection in the low PMI group, compared with 1 out of 9 patients in the normal PMI group. Among low PMI patients who had a follow-up CT scan, 62.5% (5/8) of those with a functional pancreas graft either improved or resolved sarcopenia, whereas 75.0% (3/4) of those who lost their pancreas graft continued to lose muscle mass. CONCLUSION: Sarcopenia could represent one of the predictors of pancreas graft failure and should be evaluated and potentially optimized in SPK recipients.

Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations.

It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5' splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main predictor and determinant of DSBs. Damaged introns with paused Pol II-pS5, TOP2B and XRCC4 are enriched in translocation breakpoints, and map at topologically associating domain boundary-flanking regions showing high interaction frequencies with distal loci. Thus, in unperturbed growth conditions, release of paused Pol II at specific loci and chromatin territories favors DSB formation, leading to chromosomal translocations.

Rheumatic Heart Disease Predisposing to Embolic Myocardial Infarction: A Multimodality Imaging Approach.

We report a clinical case of a 45-year-old male with a diagnosis of inferior myocardial infarction and previous history of rheumatic fever during his childhood. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram showed hypokinetic left ventricular inferolateral wall and mitral stenosis; furthermore, speckle tracking analysis revealed reduction of global longitudinal strain involving the inferior wall. A three-dimensional transesophaegeal echocardiography, performed to better characterize the anatomy of the valve and to find possible source of embolic infarct in an enlarged left atrium, showed rheumatic valvular involvement. Cardiac magnetic resonance confirmed the ischemic damage and also provided prognostic information. A multimodality imaging approach should be mandatory in patients with acute myocardial infarction and normal coronary angiography, to define possible sources of embolic infarction and to quantify myocardial damage.

Erythromycin- and copper-resistant Enterococcus hirae from marine sediment and co-transfer of erm(B) and tcrB to human Enterococcus faecalis.

An erythromycin-, copper- and cadmium-resistant isolate of Enterococcus hirae from marine sediment was shown to harbor the plasmid pRE25 and to co-transfer erm(B) and tcrB to Enterococcus faecalis JH2-2. These data highlight the scope for antibiotic resistance selection by the marine environment through heavy metals and its possible involvement in antibiotic-resistant enterococcal infections.