A time to give something back 1

Goodbye Jennifer, Arrivals and

Departures, new Chillers 2

MRC Festival of Research 3

Research Successes 4

Other news 7

Awards and Upcoming events 7

Our scientists in the limelight 8

Recent publications 9

Message from the Director

Welcome to the summer edition

of the MRC CU newsletter, in

which we look back with pride on

all our Public Engagement

endeavours over the summer,

celebrate completion of a clinical

trial, the research underpinning

which was conceived at the Unit

and, as always, showcase new

research as well as other

achievements from our staff and

students, over the last quarter of

the year.

To keep up to date with our news,

till the next edition, please visit

our Website, Facebook and

Twitter pages.

With Best Wishes,

Professor Ashok Venkitaraman.

Director, MRC Cancer Unit

A time to give something back

A chronicle of Public Engagements over the summer…

Contents Summer 2019 www.mrc-cu.cam.ac.uk

The MRC CU, and indeed the Hutch community as a whole, has always strongly

believed in a duty of collegiate support for other organisations, big and small, that

help fight cancer and other disabling conditions, especially in young people.

Spurred on by this mantra, a bunch of hardcore fitness enthusiasts embarked on

what at the start frankly seemed a little crazy. The Hutch Hoppers (that’s what

they christened themselves) comprising of Jordi, Alberto, David, Luisa, Oana,

Francois, and Steve trained tirelessly over months for The Nuclear Races - an

obstacle course spread across 90 hurdles, 12 km of running and lots of mud!

Drawing on support from the generous Hutch community and helped along by

yet another gourmet Cake Sale at the end of it all, they managed to raise more

than 1000 pounds for the Teenage Cancer Trust and the MoorHouse

School – both wonderful organisations that support young adults (coping with

cancer and speech and language difficulties, respectively). Hats off to the Hoppers

and for sure this has ushered in a new wave of enthusiasm for running, fitness and

community work. For soon after, we had the inception of the cleverly acronymed

(M)olecular (R)unning (C)lub at the Hutch whose first adventure was at the

CRUK Race for Life event in July, through which they raised more than £600.0

for cancer research. Long may this legacy of giving back last amongst us.

MRC Cancer Unit

In support of: Teenage Cancer

Trust, MoorHouse School, CRUK

Moorhouse

2

Goodbye Jennifer!

The MRC CU will dearly miss Jennifer Furman - the Hutch Research Governance and

Integrity co-ordinator, undoubtedly not just the world’s most generous RG expert cum

gourmet baker, but someone who won hearts with her

seemingly endless capacity for helping people, her passion for

her job, and her can-do spirit in all things at the Hutch. As

Jennifer moves to other challenges within the School we all

thank her for her support and extraordinary generosity of spirit

and wish her every success and happiness in her new job. HTA

has never been so delicious before - thank you!

Other recent arrivals & departures

We welcome Joao Lopes Dias (Bioinformatician), Hannah Coles, Tim Young (Research Assistants) and Rob O'Neill

(Visiting Clinician). We would like to wish Rachel de la Rue, Houda Abla, Erika Vojtasova, Pauline Bourigault and

all our work experience/summer visiting students the very best in their future careers.

The new chillers are here

After years of air-conditioning woes, courtesy ageing infrastructure, the building finally had brand new chillers

commissioned by the University. After extensive building works over the past 3 months, the new rooftop chillers

have been installed (on time!) and have so far functioned seamlessly. Hopefully a reason to celebrate with the

return of the ice-cream van soon.

Continued from page 1

On a different note ‘giving back’ was also what spurred on our researchers who visited the Sawston Village College

Junior STEM club in June to enthuse young children and give them a flavour of the excitement of research - as one kid

put it: “I enjoyed it because I was so amazed by all the tech and it was really fun. Thanks”. A big thank you to Rebecca, Jamie

and their team members for so generously devoting their time for this. Last but not least, we had our students and PIs

(Jake, Jacqui, Christian and Charlie) speaking on the theme of “Combating Cancer” at the annual ‘Pint of Science’ Festival

in May which provides a worldwide platform to ‘quench one’s thirst for knowledge’ in the comfort of one’s local pub or

café. Thank you to Jake for being lead organiser!

3

The MRC Festival of Research, 2019

Alongside promoting world class research, the MRC CU

considers it a cardinal responsibility to support the education

and training of the next generation of cancer researchers and

provide opportunities to high school students to engage in and

gain exposure to the latest cancer research and be inspired to

pursue a career in research.

Therefore, as in previous

years, as part of the MRC

Festival of Medical Research

in June, we chose to focus

on school students and

organised the Schools Open

Day. As part of this on the 19th June, sixth

form students from several local schools

were given a hands-on tour of the CU labs,

followed by a careers session with

scientists at various stages of their

research journeys. Suffices to say an

afternoon of thrilling discoveries followed

for the young visitors - perhaps aptly summed

up in one of the feedback comments: “Working in a lab seems much more

exciting and fun than (I) previously thought!” A big thank you to all who

volunteered to make this event possible.

For Festival week, our local MP, Heidi Allen was invited back to the Unit.

Heidi met with a panel comprising of

support staff, students, post-docs,

group leaders and the Director. Frank

and compelling discussions about the

future of British R&D in the current

political climate, the case for continued

funding of niche research organisations

such as the CU within the wider

landscape of cancer research across

the country and a general update on

the progress of the Unit’s Research

over the past year were the highlights

of the visit. Refreshingly, following up

on her promise last year to visit our labs, Heidi went on a tour of the building,

discovering for herself cutting edge research and equipment and stopped to

engage with students and members of staff along the way.

4

MRC Cancer Unit: Research successes

'Fingerprint database' could help to identify new cancer culprits

Somatic mutations in cancer cells, arising through cell-intrinsic and exogenous processes, mark the genome with

distinctive patterns termed mutational signatures.

In a collaboration with David Phillips, King’s

College London, Serena Nik Zainal’s group

systematically explored mutational signatures

associated with environmental agents that are

either known or suspected to be linked to cancer.

In all, 79 agents from 13 families were used to

treat human induced pluripotent stem cells

(IPSCs), including agents found in everyday

exposures like exhaust fumes, tobacco smoke,

chemical dyes and things we ingest. A highly

standardised set-up was used to ensure that all

results were comparable to one another. Cell

viability was aimed for 40-60%, functional DNA

damage response assays were obtained, and

metabolic activation was taken into

consideration. Single-cell subclones were derived

from recovered cells. In all, 324 iPSC subclones

were whole genome sequenced to seek genome-

wide mutation patterns. Computational analysis

highlighted pathognomonic “fingerprints” of 41

environmental agents including 41 substitution patterns, 6 double-substitution and 8 indel signatures. New

mechanistic insights were gained into mutagenesis and learned about contributions of DNA repair pathways to

the final mutational outcome. Critically, these results will serve as a reference set of mutational signatures with

public health and surveillance implications. In the future, when all tumours are sequenced, these reference

catalogues of mutational signatures can be used to understand whether environmental mutagens are culprits in

the development of a patient’s tumour.

The study entitled A Compendium of Mutational Signatures of Environmental Agents has been published in

Cell.

It has received wide press coverage including in newspapers like the Guardian and the Telegraph and

has also been widely discussed across social media channels and highlighted on various scientific and University

websites. A video summary of the article released by Cell Press is available here:

https://www.youtube.com/watch?v=kzorkO2rsm8

5

Improved nanoparticles for lymph node mapping are non-disruptive to immune function

The Shields lab is involved in a long-term collaboration with Cambridge-based company Endomag, towards

the development of Carboxydextran-coated superparamagnetic iron oxide particle (SPIO)-based technologies for

use in the clinic as an alternative to radioisotopes for intraoperative lymph node (LN) mapping - an important part

of staging cancers, particularly breast cancer and

malignant melanoma. Whilst this approach has proven

to be a safe and effective alternative to radio-labeled

tracers in both European and the US clinics, the

mechanisms of transport to lymph nodes, and longer-

term impact of SPIO accumulation in tissues remained

unclear. A recent study in collaboration with the

Shields Lab, led by Luisa Pedro, identified that rapid

transport to lymph nodes was governed by mechanical

(lymph flow) rather than cell-mediated (transport

within immune cells) means. Particles were detected in

draining lymph nodes within 10 minutes of

administration and localized predominantly with

lymphatic structures. In contrast, cell-driven trafficking

to lymph nodes required 24 hours. Longer-term, SPIO

could be observed in association with macrophages,

raising the question whether this could change their

behaviour, impairing their ability to mount an

appropriate immune response when needed.

Consistent with previous reports, the study

demonstrates that although alterations in macrophage

behavior could be observed immediately after

exposure, the changes were transient, resolving to

baseline levels by day 7. Moreover, macrophages

retained the capacity to proteolytically process antigens

and respond to an inflammatory stimulus following

exposure to particles. Thus, while particles persist at

injection sites and LNs where they may be sampled by macrophages, this study indicated that after an initial

perturbation, carboxydextran-coated SPIO nanoparticles within macrophages conferred no long-term disruption

to macrophage phenotype or functional capacity.

The study entitled Impact of Locally Administered Carboxydextran‐Coated Super‐Paramagnetic Iron

Nanoparticles on Cellular Immune Function has been published in Small.

Antioxidants prevent mutation harbouring cells in the oesophagus from progressing after

Low Dose Radiation exposure

Low doses of radiation, such as from medical imaging, are considered safe as they cause little DNA damage and

apparently minimal effect on long-term health. However, a recent study involving Phil Jones’ group in

collaboration with Christian Frezza finds that exposure to low doses of radiation, equivalent to three CT

scans, may promote the spread of cancer-capable cells in healthy tissue. The team found that such radiation

exposure increases the population of cells with mutations in p53. However, giving the mice an antioxidant before

radiation promoted the growth of healthy cells, which outcompeted and replaced the p53 mutant cells.

Researchers from the Jones group have previously shown how normal tissues, like skin, are battlefields where

mutant cells compete for space against healthy cells. Using mouse oesophageal tissue as a model system, this new

study shows that low doses of radiation weigh the odds in favour of cancer-capable mutant cells in the oesophagus.

Continued from page 4

6 Exposure to a 50 milligray dose of radiation,

equivalent to three or four CT scans, would result

in the p53 mutant cells spreading and

outcompeting healthy cells. However, giving these

mice an over-the-counter antioxidant – N-Acetyl

Cysteine (NAC) before exposure to the same level

of radiation gave normal cells the boost needed to

outcompete and eradicate the p53 mutant cells.

Interestingly, the antioxidant alone without

exposure to radiation did not help normal cells

outnumber the mutant clones. The study highlights

the effects of low doses of radiation and the risks

it may carry and also offers the possibility of

developing safer preventative measures to lower

the risk of developing cancer by boosting healthy

cells to outcompete and eliminate cancer-capable

cells.

The study entitled Outcompeting p53-Mutant

Cells in the Normal Esophagus by Redox Manipulation has been published in Cell Stem Cell.

Continued from page 5

7

Awards & Conferences In June, Karol Nowicki-Osuch, post-doc in the

Fitzgerald group, was awarded a Canada-UK

Postdoctoral Fellowships for Innovation and

Entrepreneurship. The exchange fellowship will

enable Karol to work on the Global Challenges

together with the Centre for Global Equality whilst

developing entrepreneurial and leaderships skills in

an international context. Well done Karol!

Saif Ahmad, former student and current associate

of the Venkitaraman lab, was also a recipient of the

same fellowship last year. As part of this award,

working in tandem with the Borysiewicz Biomedical

Sciences Fellowship (which also started last year),

Saif was part of a team of post-docs from diverse

backgrounds whose mission was to contribute to a

United Nations Sustainable Development Goal. The

main part of the project involves travelling to

Argentina this summer and working with

Argentinian Universities and Government to provide

an outreach programme on air pollution. Saif and his

team members organised interactive events and

training for volunteers and University students

whilst out there to introduce low-cost air pollution

sensors and then use these sensors on bikes around

Buenos Aires. The sensor was created by students

at the University of Cambridge.

Other News

The BEST3 Trials come to an

end

In one of the most successful

examples of tax payer funded basic

research from the Unit dovetailing

onto charity funded translational

efforts to benefit patients, the BEST3

clinical trials, to assess the efficacy of

the CytospongeTM test in comparison

to traditional endoscopies for the

detection of Barrett’s Oesophagus,

carried out in GP surgeries across the

country, has come to an end this

summer. 110 GP sites, 15+ hospitals

and 13000 patients on, the collection

of data - a Herculean team effort - is

now complete; the findings from the

Trial are expected in early 2020. We

wish the team the very BEST in their

efforts to promote cost effective,

convenient, early detection of a

condition that predisposes to a

potentially deadly cancer.

Royal Soc. Summer Science

Exhibition Ben Hall’s lab was

invited to this huge annual event

where they highlighted the role of

computational modelling in cancer.

Upcoming events

❖ Big Biology Day – 5 October

❖ Postdoc Retreat and welcome event

for new starters – October (date tbc)

❖ Hutch Annual Retreat – 15 Nov.

8

Our scientists in the limelight

The Unit featured in a couple of recent

special editions of the local

newspaper - The Cambridge

Independent – first, in May, in a

supplement showcasing outstanding

schools outreach efforts at the

Biomedical Campus and more recently

in its latest August edition focussing on

clinicians who bridge the world of

laboratory research, featuring Dr

Serena Nik Zainal.

9

Recent publications

Relating evolutionary selection and mutant clonal dynamics in normal epithelia. Hall MWJ, Jones PH, Hall

BA. J R Soc Interface. 2019 Jul 26;16(156):20190230. doi: 10.1098/rsif.2019.0230. Epub 2019 Jul 31. PubMed

PMID: 31362624; PubMed Central PMCID: PMC6685019.

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-

mediated metabolism. Thomas LW, Esposito C, Stephen JM, Costa ASH, Frezza C, Blacker TS, Szabadkai G,

Ashcroft M. Cancer Metab. 2019 Jul 16;7:7.doi: 10.1186/s40170-019-0200-4. eCollection 2019. PubMed PMID:

31346464; PubMed Central PMCID: PMC6632184.

How do mutations affecting the breast cancer genes BRCA1and BRCA2 cause cancer susceptibility?

Venkitaraman AR. DNA Repair (Amst). 2019 Jul 8:102668. doi:10.1016/j. dnarep.2019.102668. [Epub ahead of

print] Review. PubMed PMID:31337537.

Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation. Fernandez-Antoran D,

Piedrafita G, Murai K, Ong SH, Herms A, Frezza C, Jones PH. Cell Stem Cell. 2019 Jul 9. pii: S1934-

5909(19)30275-9. doi: 10.1016/j.stem.2019.06.011. [Epub ahead of print] PubMed PMID: 31327664.

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic

vulnerabilities in esophageal adenocarcinoma. Mourikis TP, Benedetti L, Foxall E, Temelkovski D, Nulsen J,

Perner J, Cereda M, Lagergren J, Howell M, Yau C, Fitzgerald RC, Scaffidi P; Oesophageal Cancer Clinical and

Molecular Stratification (OCCAMS) Consortium, Ciccarelli FD. Nat Commun. 2019 Jul 15;10(1):3101. doi:

10.1038/s41467-019-10898-3. PubMed PMID: 31308377; PubMed Central PMCID: PMC6629660.

Acute Iron Deprivation Reprograms Human Macrophage Metabolism and Reduces Inflammation In Vivo.

Pereira M, Chen TD, Buang N, Olona A, Ko JH, Prendecki M, Costa ASH, Nikitopoulou E, Tronci L, Pusey CD,

Cook HT, McAdoo SP, Frezza C, Behmoaras J. Cell Rep. 2019 Jul 9;28(2):498-511.e5. doi:

10.1016/j.celrep.2019.06.039. PubMed PMID: 31291584; PubMed Central PMCID: PMC6635384.

Mitochondrial DNA: the overlooked oncogenome? Gammage PA, Frezza C. BMC Biol. 2019 Jul 8;17(1):53.

doi: 10.1186/s12915-019-0668-y. Review. PubMed PMID: 31286943; PubMed Central PMCID: PMC6615100.

Ductal carcinoma in situ: to treat or not to treat, that is the question. van Seijen M, Lips EH, Thompson AM,

Nik-Zainal S, Futreal A, Hwang ES, Verschuur E, Lane J, Jonkers J, Rea DW, Wesseling J; PRECISION team. Br J

Cancer. 2019 Aug;121(4):285-292. doi: 10.1038/s41416-019-0478-6. Epub 2019 Jul 9. Review. PubMed PMID:

31285590; PubMed Central PMCID: PMC6697179.

A practical guide for mutational signature analysis in hematological malignancies. Maura F, Degasperi A,

Nadeu F, Leongamornlert D, Davies H, Moore L, Royo R, Ziccheddu B, Puente XS, Avet-Loiseau H, Cambell PJ,

Nik-Zainal S, Campo E, Munshi N, Bolli N. Nat Commun. 2019 Jul 5;10(1):2969. doi: 10.1038/s41467-019-11037-

8. PubMed PMID: 31278357.

Metabolite Exchange between Mammalian Organs Quantified in Pigs. Jang C, Hui S, Zeng X, Cowan AJ,

Wang L, Chen L, Morscher RJ, Reyes J, Frezza C, Hwang HY, Imai A, Saito Y, Okamoto K, Vaspoli C, Kasprenski

L, Zsido GA 2nd, Gorman JH 3rd, Gorman RC, Rabinowitz JD. Cell Metab. 2019 Jun 26. pii: S1550-

4131(19)30305-5. doi: 10.1016/j.cmet.2019.06.002. [Epub ahead of print] PubMed PMID: 31257152.

10

Feasibility of combined screening for upper gastrointestinal adenocarcinoma risk by serology and

Cytosponge testing: the SUGAR study. Xu Y, Miremadi A, Link A, Malfertheiner P, Fitzgerald RC, Bornschein J.

J Clin Pathol. 2019 Jun 24. pii: jclinpath-2019-205700. doi: 10.1136/jclinpath-2019-205700. [Epub ahead of print]

PubMed PMID: 31235543.

The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer. De Mattos-Arruda L, Sammut

SJ, Ross EM, Bashford-Rogers R, Greenstein E, Markus H, Morganella S, Teng Y, Maruvka Y, Pereira B, Rueda OM,

Chin SF, Contente-Cuomo T, Mayor R, Arias A, Ali HR, Cope W, Tiezzi D, Dariush A, Dias Amarante T, Reshef

D, Ciriaco N, Martinez-Saez E, Peg V, Ramon Y Cajal S, Cortes J, Vassiliou G, Getz G, Nik-Zainal S, Murtaza M,

Friedman N, Markowetz F, Seoane J, Caldas C. Cell Rep. 2019 May 28;27(9):2690-2708.e10.

doi:10.1016/j.celrep.2019.04.098. PubMed PMID: 31141692; PubMed Central PMCID: PMC6546974.

Barrett oesophagus. Peters Y, Al-Kaabi A, Shaheen NJ, Chak A, Blum A, Souza RF, Di Pietro M, Iyer PG, Pech

O, Fitzgerald RC, Siersema PD. Nat Rev Dis Primers. 2019 May 23;5(1):35. doi: 10.1038/s41572-019-0086-z.

Review. PubMed PMID: 31123267.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

Nones K, Johnson J, Newell F, Patch AM, Thorne H, Kazakoff SH, de Luca XM, Parsons MT, Ferguson K, Reid L,

McCart Reed AE, Srihari S, Lakis V, Davidson AL, Mukhopadhyay P, Holmes O, Xu Q, Wood S, Leonard C;

Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab);

Australian Breast Cancer Tissue Bank (ABCTB); Brisbane Breast Bank (BBB), BeesleyJ, Harris J, Barnes D,

Degasperi A, Ragan MA, Spurdle AB, Khanna KK, Lakhani SR, Pearson JV, Nik-Zainal S, Chenevix-Trench G,

Waddell N, Simpson PT. Ann Oncol. 2019 May 15. pii: mdz132. doi: 10.1093/annonc/mdz132. [Epub ahead of

print] PubMed PMID: 31090900.

Fumarate hydratase in cancer: A multifaceted tumour suppressor. Schmidt C, Sciacovelli M, Frezza C. Semin

Cell Dev Biol. 2019 May 21. pii: S1084-9521(18)30202-7. doi: 10.1016/j.semcdb.2019.05.002. [Epub ahead of print]

Review. PubMed PMID: 31085323.

Ingested asbestos in filtered beer, in addition to occupational exposure, as a causative factor in

oesophageal adenocarcinoma. Fitzgerald RC, Rhodes JM. Br J Cancer. 2019 Jun;120(12):1099-1104. doi:

10.1038/s41416-019-0467-9. Epub 2019 May 9. Review. PubMed PMID: 31068670.

Enhancing Biochemical Resolution by Hyperdimensional Imaging Microscopy. Esposito A, Venkitaraman

AR. Biophys J. 2019 May 21;116(10):1815-1822. doi: 10.1016/j.bpj.2019.04.015. Epub 2019 Apr 22. PubMed PMID:

31060813; PubMed Central PMCID: PMC6531829.

Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal

junction. Bornschein J, Wernisch L, Secrier M, Miremadi A, Perner J, MacRae S, O'Donovan M, Newton R, Menon

S, Bower L, Eldridge MD, Devonshire G, Cheah C, Turkington R, Hardwick RH, Selgrad M, Venerito M,

Malfertheiner P; OCCAMS Consortium, Fitzgerald RC. Int J Cancer. 2019 May 3. doi: 10.1002/ijc.32384. [Epub

ahead of print] PubMed PMID: 31050820.

A clinically translatable hyperspectral endoscopy (HySE) system for imaging the gastrointestinal tract.

Yoon J, Joseph J, Waterhouse DJ, Luthman AS, Gordon GSD, di Pietro M, Januszewicz W, Fitzgerald RC, Bohndiek

SE. Nat Commun. 2019 Apr 23;10(1):1902. doi: 10.1038/s41467-019-09484-4. PubMed PMID: 31015458; PubMed

Central PMCID: PMC6478902.

11

Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island

hypermethylation. Brinkman AB, Nik-Zainal S, Simmer F, Rodríguez-González FG, Smid M, Alexandrov LB, Butler

A, Martin S, Davies H, Glodzik D, Zou X, Ramakrishna M, Staaf J, Ringnér M, Sieuwerts A, Ferrari A, Morganella

S, Fleischer T, Kristensen V, Gut M, van de Vijver MJ, Børresen-Dale AL, Richardson AL, Thomas G, Gut IG,

Martens JWM, Foekens JA, Stratton MR, Stunnenberg HG. Nat Commun. 2019 Apr 15;10(1):1749. doi:

10.1038/s41467-019-09828-0. PubMed PMID: 30988298; PubMed Central PMCID: PMC6465362.

Impact of Locally Administered Carboxydextran-Coated Super-Paramagnetic Iron Nanoparticles on

Cellular Immune Function. Pedro L, Harmer Q, Mayes E, Shields JD. Small. 2019 May;15(20):e1900224. doi:

10.1002/smll.201900224. Epub 2019 Apr 15. PubMed PMID: 30985079; PubMed Central PMCID: PMC6542677.

A Compendium of Mutational Signatures of Environmental Agents. Kucab JE, Zou X, Morganella S, Joel M,

Nanda AS, Nagy E, Gomez C, Degasperi A, Harris R, Jackson SP, Arlt VM, Phillips DH, Nik-Zainal S. Cell. 2019

May 2;177(4):821-836.e16. doi: 10.1016/j.cell.2019.03.001. Epub 2019 Apr 11. PubMed PMID: 30982602; PubMed

Central PMCID: PMC6506336.

Will a Proton Pump Inhibitor and an Aspirin Keep the Doctor Away for Patients With Barrett's Esophagus?

Fitzgerald RC, Corley DA. Gastroenterology. 2019 Apr;156(5):1228-1231. doi: 10.1053/j.gastro.2019.03.001.

Epub 2019 Mar 5. PubMed PMID: 30849313.

MRC Cancer Unit

University of Cambridge

Hutchison/MRC Research Centre

Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ

Tel: 01223 763240

Email: contact@mrc-cu.cam.ac.uk

www.mrc-cu.cam.ac.uk

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