TY  - JOUR
AB  - BACKGROUND: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome. METHODS: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock. Bioinformatics yielded conserved motifs, and candidate receptors were affinity purified. In silico and in vitro approaches served to investigate possible associations between candidate receptors and calcium, a major component of skeletal muscle and bone. In vivo homing and molecular imaging (PET/MRI and SPECT/CT) studies of the most promising ligand peptide candidate were performed in the porcine model and were also confirmed in a corresponding rat model of major trauma. Optical methodologies and molecular dynamics simulations served to explore the molecular attributes of the ligand-receptor binding. FINDINGS: Nearly all molecular targets of the selected ligand peptides were calcium-dependent proteins, which become accessible upon trauma. We validated specific binding of homing peptides to these receptors in injured tissues, including CLRGFPALVC:CASQ1, CSEIGVRAC:HSP27, and CRQRPASGC:CALR. Notably, we determined that ligand peptide CRQRPASGC targets an injury-specific calcium-facilitated conformation of calreticulin, enabling specific molecular imaging of trauma. CONCLUSIONS: We conceptually propose the term "traumome" for the functional receptor repertoire that becomes readily amenable for ligand-directed targeting upon major trauma. These preclinical findings pave the way toward clinic-ready targeted theragnostic approaches in the setting of trauma. FUNDING: Major funding was provided by the Defense Advanced Research Projects Agency (DARPA).
AU  - Pasqualini, R.*
AU  - Markosian, C.*
AU  - Staquicini, D.I.*
AU  - Dobroff, A.S.*
AU  - Dodero-Rojas, E.*
AU  - Whitford, P.C.*
AU  - Barbu, E.M.*
AU  - Bronk, J.K.*
AU  - Cardó-Vila, M.*
AU  - Christianson, D.R.*
AU  - Dias-Neto, E.*
AU  - Driessen, W.*
AU  - Guzman-Rojas, L.*
AU  - Marchiò, S.*
AU  - Nunes, D.N.*
AU  - de Oliveira, F.S.*
AU  - Ozawa, M.G.*
AU  - Proneth, B.
AU  - Rangel, R.*
AU  - Smith, T.L.*
AU  - Souza, G.R.*
AU  - Staquicini, F.I.*
AU  - Tang, F.H.F.*
AU  - Baze, W.B.*
AU  - Setubal, J.C.*
AU  - Burns, J.W.*
AU  - Dubick, M.A.*
AU  - Gelovani, J.G.*
AU  - Batchinsky, A.I.*
AU  - Mogford, J.E.*
AU  - Wade, C.E.*
AU  - Holcomb, J.B.*
AU  - Burley, S.K.*
AU  - Onuchic, J.N.*
AU  - Arap, W.*
C1  - 75071
C2  - 57789
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma.
JO  - Med.
VL  - 6
IS  - 7
PB  - Cell Press
PY  - 2025
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
AU  - MAGIC (Peters, A.)
AU  - MAGIC (Grallert, H.)
C1  - 72331
C2  - 56599
SP  - 1083-1095.e6
TI  - SMIM1 absence is associated with reduced energy expenditure and excess weight.
JO  - Med.
VL  - 5
IS  - 9
PY  - 2024
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - Precision oncology aims to match the right drug(s) to the right patient. Equally important is ensuring that precision therapies are offered at the right time. Transformative, rather than incremental, outcome improvement may require treatment at diagnosis rather than in the advanced/metastatic setting after genomic evolution.
AU  - Wahida, A.
AU  - George, B.*
AU  - Kurzrock, R.*
C1  - 72766
C2  - 56724
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 1463-1465
TI  - At the right time: Moving precision therapy to newly diagnosed cancer.
JO  - Med.
VL  - 5
IS  - 12
PB  - Cell Press
PY  - 2024
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - The emergence of GIPR:GLP-1R co-agonists has heralded a renaissance of anti-obesity medication. In the recent SURMOUNT 2 trial, Garvey and colleagues set out to examine the weight loss efficacy of the GIPR:GLP-1R co-agonist tirzepatide in patients with obesity and type 2 diabetes, reporting that tirzepatide has unprecedented efficacy in a magnitude historically considered almost unattainable.1.
AU  - Novikoff, A.
AU  - Müller, T.D.
C1  - 68928
C2  - 54992
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 849-851
TI  - SURMOUNTing body weight barriers in type 2 diabetes.
JO  - Med.
VL  - 4
IS  - 12
PB  - Cell Press
PY  - 2023
SN  - 2666-6359
ER  - 

TY  - JOUR
AU  - Scheibner, K.
AU  - Lickert, H.
C1  - 64972
C2  - 51991
SP  - 279-280
TI  - Awaking sleeping islets for a cure of diabetes.
JO  - Med.
VL  - 3
IS  - 5
PY  - 2022
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - Hippich et al update their surveillance of SARS-CoV-2 antibodies in the Bavarian childhood population and show an eight-fold prevalence increase during 2021 as compared to the end of first wave in 2020. Over 50% of positive children were asymptomatic.
AU  - Hippich, M.
AU  - Sifft, P.
AU  - Zapardiel-Gonzalo, J.
AU  - Böhmer, M.M.*
AU  - Lampasona, V.*
AU  - Bonifacio, E.
AU  - Ziegler, A.-G.
C1  - 61782
C2  - 50456
SP  - 571-572
TI  - A public health antibody screening indicates a marked increase of SARS-CoV-2 exposure rate in children during the second wave.
JO  - Med.
VL  - 2
IS  - 5
PY  - 2021
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - Background: Antibody responses to virus reflect exposure and potential protection. Methods: We developed a highly specific and sensitive approach to measuring antibodies against SARS-CoV-2 for population-scale immune surveillance. Antibody positivity was defined as a dual-positive response against both the receptor binding domain and nucleocapsid proteins of SARS-CoV-2. Antibodies were measured by immuno-precipitation assays in capillary blood from 15,771 children aged 1 to 18 years living in Bavaria, Germany, and participating in a public health type 1 diabetes screening program (Clinicaltrials.gov NCT04039945), in 1,916 dried blood spots from neonates in a Bavarian screening study (Clinicaltrials.gov NCT03316261), and in 75 SARS-CoV-2 positive individuals. Virus positive incidence was obtained from Bavarian health authority data. Findings: Dual-antibody positivity was detected in none of 3887 children in 2019 (100% specificity) and 73 of 75 SARS-CoV-2 positive individuals (97.3% sensitivity). Antibody surveillance in children during 2020 resulted in frequencies of 0.08% in January to March, 0.61% in April, 0.74% in May, 1.13% in June and 0.91% in July. Antibody prevalence from April 2020 was six-fold higher than the incidence of authority-reported cases (156 per 100,000 children), showed marked variation between the seven Bavarian regions (P<0.0001), and was not associated with age or sex. Transmission in children with virus-positive family members was 35%; 47% of positive children were asymptomatic. No association with type 1 diabetes autoimmunity was observed. Antibody frequency in newborns was 0.47%. Conclusion: We demonstrate the value of population-based screening programs for pandemic monitoring. Funding: The work was supported by funding from the BMBF (FKZ01KX1818).
AU  - Hippich, M.
AU  - Holthaus, L.
AU  - Assfalg, R.*
AU  - Zapardiel-Gonzalo, J.
AU  - Kapfelsperger, H.
AU  - Heigermoser, M.
AU  - Haupt, F.
AU  - Ewald, D.A.*
AU  - Welzhofer, T.C.*
AU  - Marcus, B.A.*
AU  - Heck, S.
AU  - Koelln, A.
AU  - Stock, J.
AU  - Voss, F.
AU  - Secchi, M.*
AU  - Piemonti, L.*
AU  - Rosa, K.*
AU  - Protzer, U.
AU  - Boehmer, M.*
AU  - Achenbach, P.
AU  - Lampasona, V.*
AU  - Bonifacio, E.
AU  - Ziegler, A.-G.
C1  - 60650
C2  - 49561
SP  - 149-163.e4
TI  - Public health antibody screening indicates a six-fold higher SARS-CoV-2 exposure rate than reported cases in children.
JO  - Med.
VL  - 2
IS  - 2
PY  - 2021
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - The discovery of insulin a century ago changed the lives of millions of individuals suffering from diabetes, paving the way for long-term survival. While the availability of recombinant insulin for hormone replacement therapy has served extremely well to help control blood glucose in diabetes, there remains significant room for further improvements for an ultimate “cure” for diabetes patients. In this review, we celebrate the 100th anniversary of the discovery of insulin and consolidate the key milestones and advances in the development of recombinant human insulin. We then summarize recent and current technological developments in terms of insulin gene- and cell-replacement therapies that are promising in greater therapeutic potential. We envision that the next era of insulin replacement therapies will effectively treat diabetes and serve our patients even better for the next century to come.
AU  - Lau, H.H.*
AU  - Gan, S.U.*
AU  - Lickert, H.
AU  - Shapiro, A.M.J.*
AU  - Lee, K.O.*
AU  - Teo, A.K.K.*
C1  - 64097
C2  - 51690
SP  - 1138-1162
TI  - Charting the next century of insulin replacement with cell and gene therapies.
JO  - Med.
VL  - 2
IS  - 10
PY  - 2021
SN  - 2666-6359
ER  - 

TY  - JOUR
AB  - In this review, we bring our personal experiences to showcase insulin from its breakthrough discovery as a life-saving drug 100 years ago to its uncovering as the autoantigen and potential cause of type 1 diabetes and eventually as an opportunity to prevent autoimmune diabetes. The work covers the birth of insulin to treat patients, which is now 100 years ago; the development of human insulin, insulin analogs, devices, and the way into automated insulin delivery; the realization that insulin is the primary autoimmune target of type 1 diabetes in children; novel approaches of immunotherapy using insulin for immune tolerance induction; the possible limitations of insulin immunotherapy; and an outlook on how modern vaccines could remove the need for another 100 years of insulin therapy.
AU  - Ziegler, A.-G.
AU  - Danne, T.*
AU  - Daniel, C.
AU  - Bonifacio, E.
C1  - 63248
C2  - 51397
SP  - 1120-1137
TI  - 100 Years of insulin: Lifesaver, immune target, and potential remedy for prevention.
JO  - Med.
VL  - 2
IS  - 10
PY  - 2021
SN  - 2666-6359
ER  -