Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron.

Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.

Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation.

The eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the egg's vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with the eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission.

Talquetamab in multiple myeloma.

Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.

Syndecan-4 is required for early-stage repair responses during zebrafish heart regeneration.

BACKGROUND: The healing process after a myocardial infarction (MI) in humans involves complex events that replace damaged tissue with a fibrotic scar. The affected cardiac tissue may lose its function permanently. In contrast, zebrafish display a remarkable capacity for scar-free heart regeneration. Previous studies have revealed that syndecan-4 (SDC4) regulates inflammatory response and fibroblast activity following cardiac injury in higher vertebrates. However, whether and how Sdc4 regulates heart regeneration in highly regenerative zebrafish remains unknown. METHODS AND RESULTS: This study showed that sdc4 expression was differentially regulated during zebrafish heart regeneration by transcriptional analysis. Specifically, sdc4 expression increased rapidly and transiently in the early regeneration phase upon ventricular cryoinjury. Moreover, the knockdown of sdc4 led to a significant reduction in extracellular matrix protein deposition, immune cell accumulation, and cell proliferation at the lesion site. The expression of tgfb1a and col1a1a, as well as the protein expression of Fibronectin, were all down-regulated under sdc4 knockdown. In addition, we verified that sdc4 expression was required for cardiac repair in zebrafish via in vivo electrocardiogram analysis. Loss of sdc4 expression caused an apparent pathological Q wave and ST elevation, which are signs of human MI patients. CONCLUSIONS: Our findings support that Sdc4 is required to mediate pleiotropic repair responses in the early stage of zebrafish heart regeneration.

A quantitative framework for patient-specific collision detection in proton therapy.

BACKGROUND: Beam modifying accessories for proton therapy often need to be placed in close proximity of the patient for optimal dosimetry. However, proton treatment units are larger in size and as a result the planned treatment geometry may not be achievable due to collisions with the patient. A framework that can accurately simulate proton treatment geometry is desired. PURPOSE: A quantitative framework was developed to model patient-specific proton treatment geometry, minimize air gap, and avoid collisions. METHODS: The patient's external contour is converted into the International Electrotechnique Commission (IEC) gantry coordinates following the patient's orientation and each beam's gantry and table angles. All snout components are modeled by three-dimensional (3D) geometric shapes such as columns, cuboids, and frustums. Beam-specific parameters such as isocenter coordinates, snout type and extension are used to determine if any point on the external contour protrudes into the various snout components. A 3D graphical user interface is also provided to the planner to visualize the treatment geometry. In case of a collision, the framework's analytic algorithm quantifies the maximum protrusion of the external contour into the snout components. Without a collision, the framework quantifies the minimum distance of the external contour from the snout components and renders a warning if such distance is less than 5 cm. RESULTS: Three different snout designs are modeled. Examples of potential collision and its aversion by snout retraction are demonstrated. Different patient orientations, including a sitting treatment position, as well as treatment plans with multiple isocenters, are successfully modeled in the framework. Finally, the dosimetric advantage of reduced air gap enabled by this framework is demonstrated by comparing plans with standard and reduced air gaps. CONCLUSION: Implementation of this framework reduces incidence of collisions in the treatment room. In addition, it enables the planners to minimize the air gap and achieve better plan dosimetry.

Self-reporting of Conflicts of Interest by Ophthalmology Researchers Compared with the Open Payments Database Industry Reports.

PURPOSE: To evaluate the completeness of conflict-of-interest self-reporting by ophthalmology researchers and to assess factors associated with self-reporting. DESIGN: Cross-sectional observational study. PARTICIPANTS: We evaluated articles published between January and June 2017 in Ophthalmology, JAMA Ophthalmology, the American Journal of Ophthalmology, and Investigative Ophthalmology and Visual Science. To assess more accurately the cases in which an author published multiple articles, we defined a unit of analysis, authorship, for which each author of each article is a unique data point. To enable comparison with the Open Payments Database (OPD), we only included United States physician authorships. METHODS: For each authorship, we defined self-reported relationships as the companies listed in the article's conflict-of-interest disclosures. Based on journal policies, we defined OPD-reported relationships as the list of companies that reported payments to the author within 36 months before submission. MAIN OUTCOME MEASURES: For each authorship, we assessed the proportion of OPD-reported relationships that were self-reported. The primary measurement was the proportion of authorships reporting none of their OPD-reported relationships. RESULTS: Of the 660 total authorships (486 unique authors), 413 authorships (63%) reported none of their OPD-reported relationships, 112 (17%) reported some of them, 9 (1%) reported all of them, and 126 (19%) had 0 relationships. The proportion of authorships reporting none of their relationships did not differ significantly between journals that required reporting of all relationships compared with journals that required reporting only of relevant relationships (adjusted percentage, 61.4% vs. 64.3%; P = 0.46). Authorships with more dollars received during the reporting period showed higher rates of self-reporting (P < 0.001). CONCLUSIONS: Even among journals that required complete reporting, self-reporting was low compared with an industry-maintained database of financial relationships. Deficiencies in reporting may undermine confidence in self-reporting and may compromise the transparency that is needed to interpret research results fairly. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Activity of N-phenylbenzamide analogs against the neglected disease pathogen, Schistosoma mansoni.

For the Schistosoma mansoni flatworm pathogen, we report a structure-activity relationship of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross-screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast-acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h. Against HEK 293 mammalian cells, both compounds exhibited high CC50 values (9.8 ± 1.6 and 11.1 ± 0.2 µM respectively) which could translate to comfortable selectivity. When evaluated in a concentration-response format, compound 9 was active in the nanomolar range (EC50 = 80 nM), translating to a selectivity index of 123 over HEK 293 cells. The data encourage the further investigation of N-phenylbenzamides as antischistosomals.

Structure-activity relationship of dibenzylideneacetone analogs against the neglected disease pathogen, Trypanosoma brucei.

Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC50 values. A structure-activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC50 values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.

Early detection of myocardial ischemia in resting ECG: analysis by HHT.

BACKGROUND: Exercise electrocardiography (ECG) is a noninvasive test aiming at producing ischemic changes. However, resting ECG cannot be adopted in diagnosing myocardial ischemia till ST-segment depressions. Therefore, this study aimed to detect myocardial energy defects in resting ECG using the Hilbert-Huang transformation (HHT) in patients with angina pectoris. METHODS: Electrocardiographic recordings of positive exercise ECG by performing coronary imaging test (n = 26) and negative exercise ECG (n = 47) were collected. Based on the coronary stenoses severity, patients were divided into three categories: normal, < 50%, and ≥ 50%. During the resting phase of the exercise ECG, all 10-s ECG signals are decomposed by HHT. The RT intensity index, composed of the power spectral density of the P, QRS, and T components, is used to estimate the myocardial energy defect. RESULTS: After analyzing the resting ECG using HHT, the RT intensity index was significantly higher in patients with positive exercise ECG (27.96%) than in those with negative exercise ECG (22.30%) (p < 0.001). In patients with positive exercise ECG, the RT intensity index was gradually increasing with the severity of coronary stenoses: 25.25% (normal, n = 4), 27.14% (stenoses < 50%, n = 14), and 30.75% (stenoses ≥ 50%, n = 8). The RT intensity index of different coronary stenoses was significantly higher in patients with negative exercise ECG, except for the normal coronary imaging test. CONCLUSIONS: Patients with coronary stenoses had a higher RT index at the resting stage of exercise ECG. Resting ECG analyzed using HHT could be a method for the early detection of myocardial ischemia.

Selinexor therapy for multiple myeloma and non-Hodgkin lymphomas.

PURPOSE OF REVIEW: In this review we highlight the most recent studies furthering the clinical development of selinexor, a novel exportin-1 inhibitor, for the treatment of multiple myeloma and non-Hodgkin lymphomas. RECENT FINDINGS: Three pivotal trials, the SADAL trial for diffuse large B-cell lymphoma, and the BOSTON and selinexor treatment of refractory myeloma trials for multiple myeloma, have recently led to the regulatory approval of selinexor monotherapy or combination regimens. They are complemented by several earlier phase clinical trials with iterative combinations, adding selinexor to novel therapies and cytotoxic chemotherapy regimens at various stages in the disease courses. In some, selinexor appears synergistic, occasionally overcoming treatment refractoriness, whereas in other situations appears additive. Consistent issues with tolerability are seen across trials, although consensus guidelines on their preemption and management have recently been adopted which may improve treatment success. While comparative data are lacking, the efficacy of selinexor-based regimens does not approach that of contemporaneous cellular and immunotherapies. SUMMARY: Selinexor is a novel and potentially synergistic therapy for lymphoid malignancies, although requires refined supportive measures and strategies to improve its efficacy. Likely, for continued success, it will need to identify niches that complement recent advances, such as bridging to cellular therapies or maintenance thereafter.

Preprocedural features of patients under antihypertensive drugs may help identify responders to renal denervation: a hypothesis-generating study.

BACKGROUND: Renal denervation (RDN) is effective to lower systolic blood pressure (SBP) in essential hypertension. However, patient selection under medications remains an important unmet clinical need. METHODS: This multicenter study aimed at observing whether preprocedural features associated with increased renin-angiotensin-aldosterone activity influence RDN response. This study enrolled the patients who underwent RDN for uncontrolled hypertension. Medical records were reviewd and patients were divided into 2 groups depending by meeting any of the following conditions prior to RDN: (1) >10 mmHg of office SBP reduction after aldosterone inhibition, (2) aldosterone-renin ratio >30 or (3) slow flow on the renal angiogram. RDN responders were defined by a reduction in 24-hour mean ≥6 mmHg or by ≥1 class of antihypertensive drug withdraw. RESULTS: A total of 46 patients were enrolled, of which 27 (59%) were in control group A and 19 (41%) in group B. The baseline age, gender, office and 24-hour SBP (mean 140.0 ± 12.8 mmHg vs. 144.0 ± 16.5 mmHg, p = 0.577) were comparable, while the number of prescribed drug classes was fewer in group A (4.0 ± 1.3 vs. 4.9 ± 0.9, p = 0.014). The proportion patients with prescribed aldosterone antagonist or high aldosterone-renin ratios were higher in group B. At 12 months post RDN, the results were significantly better in group B in terms of mean change in office SBP (12.4 ± 23.5 mmHg vs. 29.9 ± 25.5 mmHg, p = 0.046) and the proportion of RDN responders (51.9% vs. 89.5%, p < 0.001). CONCLUSION: RDN was more effective in patients with any of 3 clinical indices.

The autonomic balance of heart rhythm complexity after renal artery denervation: insight from entropy of entropy and average entropy analysis.

BACKGROUND: The current method to evaluate the autonomic balance after renal denervation (RDN) relies on heart rate variability (HRV). However, parameters of HRV were not always predictive of response to RDN. Therefore, the complexity and disorder of heart rhythm, measured by entropy of entropy (EoE) and average entropy (AE), have been used to analyze autonomic dysfunction. This study evaluated the dynamic changes in autonomic status after RDN via EoE and AE analysis. METHODS: Five patients were prospectively enrolled in the Global SYMPLICITY Registry from 2020 to 2021. 24-h Holter and ambulatory blood pressure monitoring (ABPM) was performed at baseline and 3 months after RDN procedures. The autonomic status was analyzed using the entropy-based AE and EoE analysis and the conventional HRV-based low frequency (LF), high frequency (HF), and LF/HF. RESULTS: After RDN, the ABPM of all patients showed a significant reduction in blood pressure (BP) and heart rate. Only AE and HF values of all patients had consistent changes after RDN (p < 0.05). The spearman rank-order correlation coefficient of AE vs. HF was 0.86, but AE had a lower coefficient of variation than HF. CONCLUSIONS: Monitoring the AE and EoE analysis could be an alternative to interpreting autonomic status. In addition, a relative change of autonomic tone, especially an increasing parasympathetic activity, could restore autonomic balance after RDN.

Prognostic superiority of global longitudinal strain beyond four-tiered ventricular hypertrophy in asymptomatic individuals.

BACKGROUND: This study aims to explore the clinical correlates of myocardial deformations using speckle-tracking algorithm and to determine the prognostic utility of such measures in asymptomatic ethnic Chinese population. METHODS: Global longitudinal (GLS), circumferential strain (GCS), and torsion were analyzed using featured tissue-tracking algorithm among 4049 symptom-free ethnic Chinese population. Hypertrophy (LVH) was classified into 4 tiers: indeterminate, dilated, thick and thick/dilated, by gender-stratified partition of end-diastolic volume index (EDVi) and LV mass/EDV0.67. RESULTS: LVH (7.3%) showed substantially lower GLS (-20.3 ± 1.82% vs. -18.9 ± 2.08%) yet higher torsion (2.20 ± 0.90 vs. 2.39 ± 1.01, p < 0.001) than non-LVH participants. Those with thick LVH (n = 123) were more obese, had higher blood pressure and increased high-sensitivity C-reactive protein (hs-CRP); with dilated/thick LVH (n = 26) group demonstrating highest pro-brain natriuretic peptide (NT-proBNP) and worse GLS compared to indeterminate-/non-LVH groups. There were independent associations among larger EDVi, higher NT-proBNP and decreased torsion, and among greater LV mass/EDV0.67, worse GLS, greater GCS/torsion and hs-CRP. Over a median of 2.3 years (IQR: 1.2-4.8), the dilated, thick, and dilated/thick LVH categorizations were associated with higher risk of composite all-cause death and heart failure (HF) compared to non-LVH (adjusted hazard ratio [HR]: 3.65, 3.72, 6.01, respectively, all p < 0.05). Per 1% GLS reduction was independently associated with higher risk (adjusted HR: 1.31, p < 0.001) and improved risk prediction (p ≤ 0.001 by integrated discrimination improvement [IDI]: 3.5%, 95% CI: 1.5%-5.6%, and continuous net reclassification improvement [NRI]: 42.3%, 95% CI: 24.0%-60.6%) over LVH. CONCLUSION: GLS improved risk stratification of four-tiered classification of LVH in asymptomatic ethnic Chinese.

Synergistic Effect of Simultaneous versus Sequential Combined Treatment of Histone Deacetylase Inhibitor Valproic Acid with Etoposide on Melanoma Cells.

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated as a potential sensitizer of chemotherapy drugs on various metastatic cancers, including advanced melanoma. In this study, we explored whether VPA could serve as an effective sensitizer of chemotherapy drug etoposide (ETO) on B16-F10 and SK-MEL-2-Luc melanoma cell lines in response to drug-induced DNA damages. Our results demonstrated that the VPA-ETO simultaneous combined treatment and ETO pretreated sequential combined treatment generated higher inhibitory effectivities than the individual treatment of each drug. We found the VPA-ETO simultaneous combined treatment contributed to the synergistic inhibitory effect by the augmented DNA double-strand breaks, accompanied by a compromised homologous recombination activity. In comparison, the ETO pretreated sequential combined treatment led to synergistic inhibitory effect via enhanced apoptosis. Surprisingly, the enhanced homologous recombination activity and G2/M phase arrest resulted in the antagonistic effect in both cells under VPA pretreated sequential combined treatment. In summary, our findings suggested that sequential order and effective dose of drug administration in VPA-ETO combination therapy could induce different cellular responses in melanoma cells. Such understanding might help potentiate the effectiveness of melanoma treatment and highlight the importance of sequential order and effective dose in combination therapy.

Effects of lorcaserin on cardiometabolic risk factors in overweight and obese patients: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Lorcaserin is a selective serotonin 2c receptor agonist approved as an anti-obesity agent. The additional cardiometabolic benefits associated with lorcaserin have not been conclusively established. The aim of the systematic review and meta-analysis is to examine the effects of lorcaserin on blood pressure, heart rate and other metabolic parameters in overweight and obese patients from randomized controlled clinical trials (RCTs). METHODS: A literature search was conducted on PubMed, EMBASE and Cochrane Central using the search terms 'lorcaserin' and 'randomized controlled trials' without language restrictions. RCTs with a follow-up period of at least 24 weeks were included in the meta-analysis. RESULTS AND DISCUSSION: Six studies with 9452 patients in the lorcaserin group and 9392 patients in the placebo group were included. Compared with placebo, lorcaserin not only reduced weight, BMI and waist circumference but also improved SBP, DBP, heart rate, LDL, triglycerides, fasting plasma glucose and HbA1c. Our findings suggest that lorcaserin has trivial though consistent and favourable effects on blood pressure, heart rate and metabolic syndrome. WHAT IS NEW AND CONCLUSION: Lorcaserin improved all cardiometabolic parameters modestly in addition to its weight loss effect in overweight and obese patients. More research is needed to determine its long-term cardiovascular benefits.

Relations between baseline burden, maximum duration, and relative reduction of atrial fibrillation: Insights from continuous monitoring in rhythm control.

INTRODUCTION: Cardiac implantable electronic devices (CIEDs) can measure atrial fibrillation (AF) early; however, the timing for administering antiarrhythmic drugs (AADs) to suppress AF remains unclear. This study aimed to investigate the association between baseline values and changes after AAD in terms of relative reduction of AF burden (RRAB) and maximum AF duration (RRMD). METHODS: This multicenter retrospective study screened all patients with nonpermanent AF who had dual-chamber pacemakers and only enrolled those receiving a naive AAD between September 2009 and December 2014. AF burden and maximum duration were calculated using CIED at 0 and 3 to 6 months after starting rhythm control. All the enrolled patients were divided into four groups according to baseline AF burden. RRAB and RRMD were monitored using CIEDs. RESULTS: Overall, 145 eligible subjects received a naive AAD for nonpermanent AF. The mean RRAB in the four groups (AF burden <1%, 1%-4%, 4%-18%, and ≥18%) were -65.3%, -46.4%, -34.7%, and -27.9% (P = 0.005), respectively. Mean RRMD were -26.8%, -12.4%, 4.2%, and 6.0%, respectively ( P = 0.006). Multivariate analysis revealed that the lowest baseline AF burden (<1%) was significantly associated with greater RRAB, which was not observed in the RRMD model. CONCLUSIONS: Lower baseline AF burden was associated with greater RRAB by AADs. Our finding suggests that rhythm control should be started in the early stage to achieve better responses to AADs.

Effect of Radiofrequency-Based Renal Denervation: The Impact of Unplanned Medication Change from a Systematic Review and Meta-Analysis.

BACKGROUND: Catheter-based renal denervation (RDN) has emerged as a promising treatment option for hypertension. However, randomized controlled trials (RCTs) have reported conflicting results on blood pressure (BP) reduction. Patient- and procedure-related confounders have been implied as the potential sources of inconsistent BP responses. We aimed to investigated whether unplanned and frequent medication changes in RDN studies affected the BP response to RDN by conducting sensitivity and subgroup analyses, according to antihypertensive medication change rates in a meta-analysis of RCTs. METHODS: We searched the PUBMED, EMBASE, and COCHRANE databases up to May 2018. RCTs that studied the effects of RDN on hypertensive patients were included. A meta-analysis was carried out using RevMan 5.3. RESULTS: A total of 12 studies were included, of which four fulfilled the inclusion criteria of < 10% medication change rate in our review. Subgroup meta-analyses of the four RCTs with < 10% medication change rates showed statistically significant reductions of 6.07 mmHg and 7.12 mmHg in 24-hour and office systolic BP, respectively. The 24-hour and office diastolic BP were also reduced (mean difference = -3.89 mmHg and -4.27 mmHg, respectively). These subgroup analyses had no heterogeneity (I2 = 0%). In contrast, the pooled analysis of the 12 studies and the subgroup analysis of eight studies with > 10% medication change rates both had a high level of heterogeneity and no significant BP reduction. CONCLUSIONS: The effectiveness of RDN was demonstrated across a broad range of antihypertensive medications used at baseline after removing the confounder of unplanned medication changes.

Single Drop Whole Blood Diagnostics: Portable Biomedical Sensor for Cardiac Troponin I Detection.

Detection of disease biomarkers from whole blood is very important in disease prevention and management. However, new generation assays like point-of-care or mobile diagnostics face a myriad of challenges in detecting proteins from whole blood. In this research, we have designed, fabricated, and characterized a portable biomedical sensor for the detection of cardiac troponin I (cTnI) directly from whole blood, without sample pretreatments. The sensing methodology is based on an extended gate electrical double layer (EDL) gated field effect transistor (FET) biosensor that can offer very high sensitivity, a wide dynamic range, and high selectivity to target analyte. The sensing methodology is not impeded by electrostatic screening and can be applied to all types of FET sensors. A portable biomedical system is designed to carry out the diagnostic assay in a very simple and rapid manner, that allows the user to screen for target protein from a single drop of blood, in 5 min. This biomedical sensor can be used in hospitals and homes alike, for early detection of cTnI which is a clinical marker for acute myocardial infarction. This sensing methodology could potentially revolutionize the modern health care industry.

Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0.007 in early and P = 0.0048 in late clinical stages). Activated pYGIV in the cytoplasm had the greatest prognostic impact in late clinical stages (P = 0.006). Furthermore, we found that the prognostic impacts of cytoplasmic pYGIV and nuclear tGIV were additive (hazard ratio 19.0548; P = 0.0002). Surprisingly, this additive effect of nuclear tGIV/cytoplasmic pYGIV was observed in human epidermal growth factor receptor 2-positive tumors (hazard ratio 16.918; P = 0.0005) but not in triple-negative breast cancers. In triple-negative breast cancers, tGIV and cytoplasmic pYGIV had no prognostic impact; however, membrane-association of pYGIV carried a poor prognosis (P = 0.026). Both tGIV and pYGIV showed no correlation with clinical stage, tumor size, pathologic type, lymph node involvement, and BRCA1/2 status. We conclude that immunocytochemical detection of pYGIV and tGIV can serve as an effective prognosticator. On the basis of the differential prognostic impact of tGIV/pYGIV within each molecular subtype, we propose a diagnostic algorithm. Further studies on larger cohorts are essential to rigorously assess the effectiveness and robustness of this algorithm in prognosticating outcome among patients with breast cancer.-Dunkel, Y., Diao, K., Aznar, N., Swanson, L., Liu, L., Zhu, W., Mi, X.-Y., Ghosh, P. Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

Calcium transcriptionally regulates the biofilm machinery of Xylella fastidiosa to promote continued biofilm development in batch cultures.

The functions of calcium (Ca) in bacteria are less characterized than in eukaryotes, where its role has been studied extensively. The plant-pathogenic bacterium Xylella fastidiosa has several virulence features that are enhanced by increased Ca concentrations, including biofilm formation. However, the specific mechanisms driving modulation of this feature are unclear. Characterization of biofilm formation over time showed that 4 mM Ca supplementation produced denser biofilms that were still developing at 96 h, while biofilm in non-supplemented media had reached the dispersal stage by 72 h. To identify changes in global gene expression in X. fastidiosa grown in supplemental Ca, RNA-Seq of batch culture biofilm cells was conducted at three 24-h time intervals. Results indicate that a variety of genes are differentially expressed in response to Ca, including genes related to attachment, motility, exopolysaccharide synthesis, biofilm formation, peptidoglycan synthesis, regulatory functions, iron homeostasis, and phages. Collectively, results demonstrate that Ca supplementation induces a transcriptional response that promotes continued biofilm development, while biofilm cells in nonsupplemented media are driven towards dispersion of cells from the biofilm structure. These results have important implications for disease progression in planta, where xylem sap is the source of Ca and other nutrients for X. fastidiosa.