A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Using biodosimetry to enhance the public health response to a nuclear incident.

Radiation Biodosimetry is a continually developing clinical diagnostic field, which focuses on biological markers that proportionally change in relationship to the amount of ionizing radiation absorbed. Examples of host marker response include changes in white cell count, specific proteins in circulation, RNAs in white blood cells, or chromosome fidelity in affected lymphocytes. Measurements of radiation biomarkers correlate with the approximate radiation dose absorbed and indirectly provide an assessment of the likelihood of developing acute radiation syndrome. The aim of this review is to summarize four biodosimetry programs that are in advanced development, later pipeline stages with funding from the Biomedical Advanced Research and Development Authority (BARDA), an agency under the Assistant Secretary for Preparedness and Response (ASPR) in the U.S. Department of Health and Human Services (HHS). With BARDA financial support, biodosimetry diagnostic assays in development will inform patient management, improve health and psychosocial outcomes, and save lives after a nuclear disaster. These tests include an SRI International developed rapid on-site screening test requiring only a finger stick of blood to triage those who have received little or no radiation from those who have received clinically significant levels of radiation and need further immediate patient management. In addition, multiple laboratory-based, high-throughput quantitative tests, currently under development by MRIGlobal, DxTerity, and ASELL, will more accurately define dose levels and possibly predict cellular and organ-damage and other longer-term effects of radiation. In the future, when clinical and analytical validation of these assays is complete, the data is reviewed by the FDA, and agency use status is obtained, rapid triage and laboratory-based biodosimetry test results will enable emergency medical teams to do the most good for the largest number of people after a nuclear blast.

First records of metal concentrations in the Pacific oyster (Crassostrea gigas) from a Southwest Atlantic estuary.

The Pacific oyster (Crassostrea gigas) is one of the world's most widespread bivalves and a suitable species for biomonitoring metals in coastal environments. In the present research, wild individuals were collected from an Argentinian estuary and the coastal beaches nearby. The concentrations of eight metals (Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn) were quantified in the soft tissues of the Pacific oyster. Among the metals, Cu, Fe and Zn reached the highest concentrations in the soft tissues over the rest of the elements. The results showed the highest values to be estuary related, with the beach site achieving the lowest values. These results possibly lie on the impact of human activities surrounding the estuary, as well as streams and rivers that outflow within it. Higher Cu and Zn levels, both port related, were mainly found toward the outer estuary. On the other hand, high levels of Cr, Fe and Mn were found toward the inner zone of the estuary, an area with sewage sludge from the cities located on the margins of the BBE. Regarding the potential risk to public health, Cu and Zn levels found in C. gigas were above national and international safety guidelines in 100% and 11% of the samples, respectively.

Parity-Engineered Light-Matter Interaction.

The concept of parity describes the inversion symmetry of a system and is of fundamental relevance in the standard model, quantum information processing, and field theory. In quantum electrodynamics, parity is conserved and large field gradients are required to engineer the parity of the light-matter interaction operator. In this work, we engineer a potassiumlike artificial atom represented by a specifically designed superconducting flux qubit. We control the wave function parity of the artificial atom with an effective orbital momentum provided by a resonator. By irradiating the artificial atom with spatially shaped microwave fields, we select the interaction parity in situ. In this way, we observe dipole and quadrupole selection rules for single state transitions and induce transparency via longitudinal coupling. Our work advances the design of tunable artificial multilevel atoms to a new level, which is particularly promising with respect to quantum chemistry simulations with near-term superconducting circuits.

Finite-time quantum entanglement in propagating squeezed microwaves.

Two-mode squeezing is a fascinating example of quantum entanglement manifested in cross-correlations of non-commuting observables between two subsystems. At the same time, these subsystems themselves may contain no quantum signatures in their self-correlations. These properties make two-mode squeezed (TMS) states an ideal resource for applications in quantum communication. Here, we generate propagating microwave TMS states by a beam splitter distributing single mode squeezing emitted from distinct Josephson parametric amplifiers along two output paths. We experimentally study the fundamental dephasing process of quantum cross-correlations in continuous-variable propagating TMS microwave states and accurately describe it with a theory model. In this way, we gain the insight into finite-time entanglement limits and predict high fidelities for benchmark quantum communication protocols such as remote state preparation and quantum teleportation.

Virulence Genes and Antimicrobial Resistance in Escherichia coli from Cheese Made from Unpasteurized Milk in Brazil.

Cow raw milk cheese is widely eaten in Brazil. These products may be contaminated with pathogenic bacteria. In this work, we investigated the presence of Escherichia coli in raw milk cheese from different States in Brazil. From 147 "Minas" cheese samples, 28 cheeses were positive for E. coli. Among 39 E. coli isolates of the cheeses, one was positive for eae and negative for bpfA and efa1/lifA using PCR, and so was classified as atypical Enteropathogenic E. coli (aEPEC). Two other isolates were positive for extraintestinal pathogenic E. coli (ExPEC) genes. The aEPEC isolate belongs to serogroup O127 and was classified in A phylogenetic group, and ExPEC isolates were found in O73:H12 (EC-2 strain) and O64474:H8 (EC-9 strain) serotype. This ExPEC belongs to A and C phylogenetic group, respectively. Most of E. coli strains belonged to Clermont phylogenetic groups A (28.2%), C, and E (23.1%). Six strains (15.4%) of E. coli were positive for group B1 and two (5.1%) for B2. E. coli isolates presented an aggregative (46.0%) and diffuse (12.6%) adherence pattern to HeLa cells, and the other isolates did not show adhesion (41.4%). Four E. coli isolates (10.3%) were shown to produce moderate biofilm. The antimicrobial resistance rate was tetracycline (25.6%), followed by ampicillin (17.9%), cefoxitin (7.7%), nalidixic acid (5.1%), and amoxicillin-clavulanic acid (2.6%). One strain was resistant to three antimicrobials (tetracycline, ampicillin, and nalidixic acid). The presence of these microorganisms, the O127 strain, and a new serogroup in Brazil is a potential risk for public health.

The c.29T>C polymorphism of the transforming growth factor beta-1 (TGFB1) gene, bone mineral density and the occurrence of low-energy fractures in patients with inflammatory bowel disease.

Gastrointestinal tract conditions are frequently associated with low bone mineral density and increased risk of fractures due to osteoporosis, the latter concerning particularly inflammatory bowel disease (IBD) patients. One of the candidate genes involved in osteoporosis is the transforming growth factor beta-1 (TGFB1) whose polymorphisms may be responsible for the development of this disease. The aim of this study was to analyse the frequency of TGFB1 polymorphic variants and determine the association between the c.29T>C TGFB1 polymorphism, and bone mineral density and fractures in IBD patients. The study subjects included 198 IBD patients [100 suffering from Crohn's disease (CD) and 98 from ulcerative colitis (UC)] and 41 healthy volunteers as a control group. Densitometric bone measurements were obtained using dual energy X-ray absorptiometry. The TGFB1 genotyping was conducted using restriction fragments length polymorphism. We conducted an analysis of genotype distribution's concordance with Hardy-Weinberg equilibrium. We found statistically significant differences in lumbar spine (L2-L4) and femoral neck BMD and T-scores between CD, UC and control subgroups. The distribution of TGFB1 polymorphic variants among CD and UC patients was concordant with Hardy-Weinberg equilibrium. There were no statistically significant differences in densitometric parameters (lumbar spine and femoral neck BMD, T-score, and Z-score) between carriers of different TGFB1 polymorphisms among IBD (CD and UC) patients nor among controls. We have found no statistically significant differences in the prevalence of low-energy fractures between groups of different TGFB1 polymorphic variant carriers. The allele dose effect, recessive effect and dominant effect analysis did not show an association between low-energy fractures and the TGFB1 polymorphisms among CD and UC patients. We have not observed an association between the c.29T>C TGFB1 polymorphic variant and the bone mineral density within the cancellous and cortical bones (L2-L4 and femoral neck, respectively), or the occurrence of fractures among the IBD patients and their family members.

Photon Statistics of Propagating Thermal Microwaves.

In experiments with superconducting quantum circuits, characterizing the photon statistics of propagating microwave fields is a fundamental task. We quantify the n^{2}+n photon number variance of thermal microwave photons emitted from a blackbody radiator for mean photon numbers, 0.05≲n≲1.5. We probe the fields using either correlation measurements or a transmon qubit coupled to a microwave resonator. Our experiments provide a precise quantitative characterization of weak microwave states and information on the noise emitted by a Josephson parametric amplifier.

Bone mineral density and the 570A>T polymorphism of the bone morphogenetic protein 2 (BMP2) gene in patients with inflammatory bowel disease: a cross-sectional study.

Finding genetic predictors of osteoporosis and fractures in patients with inflammatory bowel disease (IBD) may provide incentives for non-pharmacological actions and so improve the long-term prognosis of the patients. We analysed the incidence of BMP2 570A>T polymorphic variants and their association with bone mineral density (BMD) and the incidence of fractures in patients with IBD. The study comprised 198 IBD patients (100 with Crohn's disease (CD), and 98 with ulcerative colitis, (UC)) and 41 healthy controls. Bone densitometric analysis was carried out using the DXA method. The 570A>T polymorphisms in the BMP2 gene were genotyped using RFLP. We found significant differences in the BMD and T-scores of the lumbar spine (L2-L4) and femoral neck between the three groups. In controls and CD patients, the highest L2-L4 BMD was found in carriers of the AA variant of the BMP2 gene, while among UC patients it was the case of TT carriers. In both femoral neck and lumbar spine among UC patients, the highest BMD was observed in carriers of the TT variant of the BMP2 gene. Among patients with CD and in the control group, the highest L2-L4 BMD was found in carriers of the AA variant, whereas in UC patients, it was the case of TT homozygotes. Within the femoral neck, there were no significant differences in BMD for the carriers of individual variants of BMP2 gene polymorphism. We conclude that the 570A>T polymorphism of the BMP2 gene, no statistically significant relationship was observed between the polymorphic variant and bone mineral density or the incidence of fractures in IBD patients.

Displacement of Propagating Squeezed Microwave States.

Displacement of propagating quantum states of light is a fundamental operation for quantum communication. It enables fundamental studies on macroscopic quantum coherence and plays an important role in quantum teleportation protocols with continuous variables. In our experiments, we have successfully implemented this operation for propagating squeezed microwave states. We demonstrate that, even for strong displacement amplitudes, there is no degradation of the squeezing level in the reconstructed quantum states. Furthermore, we confirm that path entanglement generated by using displaced squeezed states remains constant over a wide range of the displacement power.

Effect of analgesia and anti-inflammatory treatment on weight gain and milk intake of dairy calves after disbudding.

AIM: To assess the effect of analgesia at disbudding on weight gain and milk intake of dairy calves. METHODS: Four disbudding protocols were used on 3- to 6-week-old Friesian-Jersey calves. Farm staff disbudded 101 calves without sedation or local analgesia, of which 51 received 20 mg meloxicam S/C. Veterinary staff disbudded 101 calves with sedation and local analgesia, of which 51 also received 20 mg meloxicam S/C. Calves were weighed before disbudding, 15 and 30 days later, and individual milk consumption was recorded for 11 days. Daily weight gain and milk consumption were analysed using mixed models and ANOVA. RESULTS: From disbudding (Day 0) to Day 15 farmer-disbudded calves receiving meloxicam grew faster (0.65 kg/day) than calves without meloxicam (0.55 kg/day; p=0.011), but an interaction between operator and meloxicam treatment (p=0.056) meant that meloxicam treatment did not increase growth rates in veterinary-disbudded calves (0.63 vs. 0.64 kg/day; p=0.872). From Days 16-30 there was no significant effect of meloxicam on growth rate, but veterinarian-disbudded calves grew faster (0.76 kg/day) than farmer-disbudded calves (0.66 kg/day; p=0.034). Overall, for the first 30 days after disbudding, if meloxicam was not used', veterinarian-disbudded calves grew faster than farmer-disbudded calves (p=0.002). However if meloxicam was used at disbudding there was no difference in growth rate between veterinarian- and farmer-disbudded calves (p=0.878). Mean cumulative milk consumption for the 11 days after disbudding was greater for calves disbudded by veterinary staff than by farm staff (p<0.001), but there was no effect of meloxicam treatment (p=0.618) and no interaction with operator (p=0.86) on cumulative milk consumption. CONCLUSIONS: Three to 6-week-old dairy calves disbudded by farm staff with no analgesia grew significantly slower over the next 15 days than farmer-disbudded calves given meloxicam, and slower over the next 30 days than veterinarian-disbudded calves given xylazine and lignocaine. However addition of meloxicam to the latter protocol had no effect on growth rate. Milk intake was significantly higher for 11 days for veterinarian- compared with farmer-disbudded calves. CLINICAL RELEVANCE: This study adds to the evidence that analgesia during disbudding is beneficial for calf productivity as well as calf welfare.

Path entanglement of continuous-variable quantum microwaves.

Path entanglement constitutes an essential resource in quantum information and communication protocols. Here, we demonstrate frequency-degenerate entanglement between continuous-variable quantum microwaves propagating along two spatially separated paths. We combine a squeezed and a vacuum state using a microwave beam splitter. Via correlation measurements, we detect and quantify the path entanglement contained in the beam splitter output state. Our experiments open the avenue to quantum teleportation, quantum communication, or quantum radar with continuous variables at microwave frequencies.

[Development and evaluation of a soccer focused complexity test]. / Entwicklung und Evaluierung eines fußballspezifischen Komplextests.

BACKGROUND: Soccer has increasingly become a technical - tactical (speed of activity!) and athletic sport over the last years. Simultaneously the new training and contest conditions result in new challenges to sports science and sports medicine evaluation. Complex, sports specific field tests for soccer exist rarely and only in low quality. OBJECTIVE: Development and evaluation of a standardised complexity test in soccer (FBKT) for assessment of the complex sports specific and league specific physical performance. MATERIALS AND METHODS: Two regional German soccer teams (Verbandsliga [VL], Oberliga [OL]) (n = 27) were assessed with FBKT. The assessment included lactate levels, heart rate as well as time and error frequency (penalty time per error: 5 s) for defined activity series at defined time points (heart rate: rest, after round 1, prior to round 2, E 0, E 2, E 6, E 10, E 14; lactate: rest, E 2, E 6, E 10, E 14). RESULTS: The heart rate (hr (max) = 200 min (-1)) and metabolic rate (lactate (max) = 17.1 mmol/l) were very excessively high and did only partially differ between the groups (heart rate difference at rest p = 0.005, prior to round 2: p = 0.014, E 6: p = 0.042). Furthermore no significant differences occurred in the following parameters: recovery potential (hr (E0 - E14): p = 0.560; lactate (Max-Min): p = 0.448), technical error (p = 0.384), sprint (p = 0.499), slalom dribbling (p = 0.310), time round 1 (p = 0.119), shots on goal (p = 0.585) and crosses (p = 0.676). Significant difference were only found in the parameters time round 2 (p = 0.004), time round 1 and round 2 (p = 0.013), overall time (running)(time + penalty)(time) (p = 0.022) and speed dribbling (p = 0.005). CONCLUSIONS: Soccer specific complex loads generate very high physical demamds. Although complex, the FBKT proved to be a practical assessment tool with high standardising potential. The FBKT gives plentiful information under competition - like conditions such as technical skills, speed, speed endurance or anaerobe capacity.

[Diagnostic tools for endurance testing in handball players]. / Diagnostik der Ausdauerleistungsfähigkeit im Handball.

BACKGROUND: The physiological demands of handball players on international level has increased during the last years mainly due to rule changes. Therefore a scientific funded training method under sports medical supervision gets more and more important. Nevertheless any only limited data are available concerning adequate tests and methods on endurance and sports related assessment of physical performance in handball. OBJECTIVE: Goal of this experimental cross sectional study was to record the endurance of handball players (regional league) in general and related to their sport. This study was performed in conjunction with the development and testing of a new handball specific complexity test (HBKT) and the use of a new lactate analysis software wesp-analysis during a treadmill test (TT). METHODS: 16 semi-professional handball players (mean age: 27.5 +/- 6.78 years) of a regional team were investigated with TT and HBKT on two different days (time delay 72 h). The parameters lactate, heart rate (TT/HBKT) and the time and rate of faults in the HBKT were recorded. RESULTS: The players showed large deficits in basic endurance capacity. There was a great performance difference within the team, especially in the lower intensity regions (< or = 3 mmol/l). Whereas the maximal heart rate was significantly higher in the TT versus the HBKT (TT: 192 +/- 8.67 min (-1) versus HBKT: 180 +/- 9.23 min (-1); p < 0.001; eta(2) = 0.794). The maximum lactate levels showed directly the opposite (10.1 +/- 2.91 mmol/l for TT versus 12.8 +/- 1.99 mmol/l for HBKT; p < 0.001, eta(2) = 0.644). Maximal run velocity (TT) and general performance (HBKT) was related on a mean level (r = -0.566). CONCLUSIONS: The results show the necessity of individual heart rate dependant basic endurance training. The correlation between the tests is a further sign for the significant importance of endurance capacity for sports performance. A comparison of these results to a higher level handball team would yield further information regarding interpretation and grading of the data. HBKT und lactate analysis software wesp-analysis showed to be practical assessment tools.

TRPC3: a multifunctional, pore-forming signalling molecule.

TRPC3 represents one of the first identified mammalian relatives of the Drosophila trp gene product. Despite intensive biochemical and biophysical characterization as well as numerous attempts to uncover its physiological role in native cell systems, this channel protein still represents one of the most enigmatic members of the transient receptor potential (TRP) superfamily. TRPC3 is significantly expressed in brain and heart and likely to play a role in both non-excitable as well as excitable cells, being potentially involved in a wide spectrum of Ca2+ signalling mechanisms. Its ability to associate with a variety of partner proteins apparently enables TRPC3 to form different cation channels in native cells. TRPC3 cation channels display unique gating and regulatory properties that allow for recognition and integration of multiple input stimuli including lipid mediators and cellular Ca2+ gradients as well as redox signals. The physiological/pathophysiological functions of this highly versatile cation channel protein are as yet barely delineated. Here we summarize current knowledge on properties and possible signalling functions of TRPC3 and discuss the potential biological relevance of this signalling molecule.

Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex.

OBJECTIVE: Members of the classical transient receptor potential protein (TRPC) family are considered as key components of phospholipase C (PLC)-dependent Ca2+ signaling. Previous results obtained in the HEK 293 expression system suggested a physical and functional coupling of TRPC3 to the cardiac-type Na+/Ca2+ exchanger, NCX1 (sodium calcium exchanger 1). This study was designed to test for expression of TRPC3 (transient receptor potential channel 3) and for the existence of a native TRPC3/NCX1 signaling complex in rat cardiac myocytes. METHODS: Protein expression and cellular distribution were determined by Western blot and immunocytochemistry. Protein-protein interactions were investigated by reciprocal co-immunoprecipitation and glutathione S-transferase (GST)-pulldown experiments. Recruitment of protein complexes into the plasma membrane was assayed by surface biotinylation. The functional role of TRPC3 was investigated by fluorimetric recording of angiotensin II-induced calcium signals employing a dominant negative knockdown strategy. RESULTS: TRPC3 immunoreactivity was observed in surface plasma membrane regions and in an intracellular membrane system. Co-immunolabeling of TRPC3 and NCX1 indicated significant co-localization of the two proteins. Both co-immunoprecipitation and GST-pulldown experiments demonstrated association of TRPC3 with NCX1. PLC stimulation was found to trigger NCX-mediated Ca2+ entry, which was dependent on TRPC3-mediated Na+ loading of myocytes. This NCX-mediated Ca2+ signaling was significantly suppressed by expression of a dominant negative fragment of TRPC3. PLC stimulation was associated with increased membrane presentation of both TRPC3 and NCX1. CONCLUSION: These results suggest a PLC-dependent recruitment of a TRPC3-NCX1 complex into the plasma membrane as a pivotal mechanism for the control of cardiac Ca2+ homeostasis.

Interobserver variation for ultrasound determination of thyroid nodule volumes.

Thyroid ultrasound is used in the routine clinical assessment and the follow-up of thyroid disorders. The follow- up of patients with thyroid nodules is mostly based on thyroid nodule volume determinations performed by different observers. However, for the judgment of treatment effects there is uncertainty about the interobserver variation of thyroid nodule volume measurements by ultrasound because there are no prospective blinded studies available comparing the interobserver variation in thyroid nodule volume measurement. The aim of our study was therefore to determine the variation of thyroid nodule volume determinations for different observers. We conducted a prospective blinded trial. Our study population consisted of 42 probands (8 men, 34 women) with an uniform distribution of thyroid nodule sizes (25 uninodular and 17 multinodular thyroid glands). We compared the results of 3 ultrasonographers with certified experience in thyroid ultrasound. The interobserver variation for the determination of thyroid nodule volume (n = 38) was 48.96% for the ellipsoid method and 48.64% for the planimetric method. The interobserver variation for determining thyroid volume (n = 40) was 23.69% for the ellipsoid method and 17.82% for the planimetric method. A regression analysis revealed that the probability for the identification of the same nodule in nodular thyroids by all sonographers is 90%, if the nodule is at least 15mm in greatest diameter. Future investigations should not describe changes in nodule volume less than 50% as therapy effects because only volume changes of at least 49% or more can be interpreted as nodule shrinkage or growth. Reporting of nodule volume modification 50% or more and lack of information for ultrasound procedures introduce a bias in studies evaluating the effects of nodule treatments. The clinical interpretation of a shrinking/growing thyroid nodule based on volume determinations by ultrasound is not well established because it is difficult to reproduce a two-dimensional image plane for follow-up studies.

Kinetics of coupling reactions that generate monothiophosphate disulfides: implications for modification of RNAs.

The inclusion of guanosine-5'-monothiophosphate (GMPS) in an in vitro transcription reaction facilitates enzymatic synthesis of an RNA transcript with a monothiophosphate group at the 5' end. A kinetic study of the modification reactions that generate monothiophosphate disulfide linkages with either 5'-GMPS alone or 5'-GMPS-primed RNA as the substrate revealed that the second-order rate constants increased as the pH was decreased. For example, when the reaction pH was lowered from 8 to 4, the k2 value for the coupling reaction between N-(6-[biotinamido]hexyl)-3'-(2'-pyridyldithio)propionamide (biotin-HPDP) and GMPS increased 67-fold from 1.84 to 123 M(-1) x s(-1). In addition to discussing a possible mechanism for coupling reactions that involve GMPS and disulfides, we also indicate conditions that are likely to be optimal for modification of the nucleophilic sulfur in 5'-GMPS-primed RNAs.

A surrogate-based approach for post-genomic partner identification.

BACKGROUND: Modern drug discovery is concerned with identification and validation of novel protein targets from among the 30,000 genes or more postulated to be present in the human genome. While protein-protein interactions may be central to many disease indications, it has been difficult to identify new chemical entities capable of regulating these interactions as either agonists or antagonists. RESULTS: In this paper, we show that peptide complements (or surrogates) derived from highly diverse random phage display libraries can be used for the identification of the expected natural biological partners for protein and non-protein targets. Our examples include surrogates isolated against both an extracellular secreted protein (TNFbeta) and intracellular disease related mRNAs. In each case, surrogates binding to these targets were obtained and found to contain partner information embedded in their amino acid sequences. Furthermore, this information was able to identify the correct biological partners from large human genome databases by rapid and integrated computer based searches. CONCLUSIONS: Modified versions of these surrogates should provide agents capable of modifying the activity of these targets and enable one to study their involvement in specific biological processes as a means of target validation for downstream drug discovery.