Quan / Qual Analyses in Clinical Research using a Second Generation Exactive High Resolution Mass Spectrometer

(1)

For Research Use Only. Not for use in Diagnostic Procedures

Lake of Geneva, Lausanne, Switzerland

quantitative

Mass Spectrometry Facility

Bertrand Rochat, PhD

Quan

/

Qual

Analyses in Clinical Research using a Second

Generation

(2)

Why a High Resolution MS in Clinical Research ?

Quantitative analyses using Triple Quadrupole MS (TQ-MS)

still representing the gold standard

Present Situation at the CHUV QMSF in Lausanne:

●

7 triple quadrupole MS installed, 1 ion trap recently replaced by an Exactive Plus MS

●

About 80-90% of all analyses performed by ion transitions (SRM) for

(3)

Why a High Resolution MS in a Research ?

« Quan / Qual » analyses by High Resolution Full Scan Acquisition (HR-FS)

a much better « picture » of the samples (troubleshooting, adducts, charge states ...)

retrospective data treatment

identification of unknowns

semi-quantitative metabolite phenotyping

Time saving

no waste of time for setting-up ion transitions

direct transfer of an analysis from HR-MS to another HR-MS

Also a Shift of Paradigm in Clinical Research ?

HR-MS replacing TQ-MS for Quan analyses ?

Key Criteria : Quantitative analyses.

(4)

The Goal of our work

Is the

Exactive Plus

HR-MS able to perform robust

quantitative

analyses in busy and productive clinical research labs

?

Quan

/Qual analyses

AS

MS

LC

N

₂

ESI

oven

(5)

Exactive Plus HR-MS, a second generation

MS

ALL

can be replaced

by a quadrupole

●

partial capabilities of ion selection

●

improved sensitivity

improved resolution

R

_max

:

Exactive 100K, 1Hz

(6)

Criteria to evaluate the Exactive Plus HR-MS

to perform Quan analyses

1.

detection selectivity in HR full scan

2.

accuracy and precision of mass determination

3.

dynamic range and linearity of Calibration curves

4.

level accuracy of UNK samples in comparison to the

quantification performed with our TQ-MS analyses

(7)

Molecules determined by Exactive and Exactive Plus MS

in our matrix samples for research

o

Antifungal drugs : caspofungin, fluconazole, itraconazole, posaconazole andv oriconazole

o

Anticancer drugs : dasatinib, imatinib, nilotinib, sorafenib sunitinib

o

Immunosupressive drugs : cylosporine, everolimus, sirolimus and tacrolimus

o

Vitamines D : 25-hydroxy-vitamin D3

o

Amino acids : 30 amino acids determined in metabolism research

►

m/z ranging from 76 (glycine) to 1220 (cyclosporine)

Sample type and sample prep.

o

Human plasma or serum

o

protein precipitation, SPE and Liquid Solid Extraction, alone or in combination

LC conditions

o

usual LC-MS mobile phases, 1D-LC or column switching (immunosuppressants)

o

C18, CN or HILIC and UHPLC or HPLC stationary phases

(8)

Criteria for evaluation

1.

2.

3.

4.

(9)

Key parameters to consider :

o

m/z value

o

biomatrix and its clean up

o

chromatographic conditions

o

concentration of the analyte

o

mass extraction window (MEW)

Resolution of

≥

20,000 to < 50,000

: HR-FS with a 5-10ppm MEW

≈

SRM

Resolution of

≥

50,000

: HR-FS with a 5-10 ppm MEW

≥

SRM selectivity

Xia YQ et al., Rapid Commun Mass Spectrom. 2011 Kaufmann A et al., Anal. Chim. Acta. 2010

Kellmann M et al, J. Am. Soc. Mass Spectrom. 2009

Van der Heeft E et al., J. Am. Soc. Mass Spectrom. 2009

How much Resolution is needed in HR - full scan

to quantify compounds in matrix samples?

(10)

1. Detection Selectivity: Resolution of the Exactive Plus

0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000

0

200

400

600

800

1'000

1'200

1'400

1'600

1'800

2'000

140,000

70,000

35,000

17,500

m/z

Resolution

(m/

m

_FWHM

)

Resolution

set at m/z 200

Mass accuracy of caffeine at m/z 195.08765

N=100; 10 min acquisition time just post mass calibration

Resolution set at mass accuracy [ppm] precision (SD) [ppm] 140,000 -0.3 0.20 70,000 -0.1 0.16 35,000 -0.2 0.19 17,500 -0.4 0.17

(11)

Measured

Mass Resolution and Acquisition Rates on Exactive Plus

Resolution set at m/z 200

m/z

140'000

70'000

35'000

17'500

195

153'027

74'302

39'073

19'054

393

105'625

54'750

26'884

13'513

753

77'520

39'996

19'948

10'034

1022

66'686

34'532

17'053

8'608

Acq. Rate (Hz)

1.8

3.7

7.2

13.2

HR-FS

HR-MS

ALL

2.9 Hz

Compatible with Quan/Qual UPLC analyses

HR-FS

Immunosupressants

Vitamine D

(12)

1. Detection selectivity in HR full scan

R

el

a

ti

v

e

A

b

u

n

d

a

n

ce

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Time [min]

Fluconazole

Itraconazole

Posaconazole

Voriconazole

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time [min]

R

el

a

ti

v

e

A

b

u

n

d

a

n

ce

0 50 100 0 50 100 0 50 100 0 50 100

Ciclosporine A

Everolimus

Sirolimus

Tacrolimus

0 50 100 0 50 100 0 50 100 0 50 100

LC - Exactive - MS chromatograms of LLOQ extracted serum and plasma

samples

(13)

0 2 4 6 8 10 12 14 16 18

Time [min]

0 50 100 0 50 100 0 50 100 0 50 100

R

e

la

ti

v

e

A

b

u

n

d

a

n

c

e

Dasatinib

Imatinib

Nilotinib

Sorafenib

1. Detection selectivity in HR full scan

LC - Exactive - MS chromatograms

of LLOQ extracted plasma samples

3-epi-25-OH-Vit-D3 25-OH-Vit-D3 0 1 2 3 4 5 6 7 8 9 10 11 12 0 50 100 0 50 100 0 50 100 0 50 100 0 50 100 6.64 6.29 7.65 IS : D₃-25-OH-Vit-D3 25-OH-Vit-D2 IS : D₆-3-epi-25-OH-Vit-D3 24,25-OH-Vit-D3

Time [min]

LC - Exactive Plus MS

chromatograms of ULOQ extracted

plasma samples

(14)

Selected amino acids from LC-HRMS chromatograms from a plasma extract

RT:7.50 - 14.00SM:5B 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e0 50 1000 50 1000 50 100 NL: 1.88E6 m/z= 126.02123-126.02375 MS 120420_11 NL: 4.24E6 m/z= 166.08517-166.08849 MS 120420_11 NL: 3.91E6 m/z= 132.10059-132.10323 MS 120420_11 NL: 1.28E6 m/z= 182.07935-182.08299 MS 120420_11 NL: 8.85E4 m/z= 150.05683-150.05983 MS 120420_11 NL: 1.80E6 m/z= 118.08508-118.08744 MS 120420_11 NL: 2.56E5 m/z= 120.06432-120.06672 MS 120420_11 RT:13.50 - 17.50SM:5B 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e 0 50 1000 50 1000 50 100 NL: 1.64E5 m/z= 106.04881-106.05093 MS 120420_11 NL: 9.98E5 m/z= 90.05406-90.05586 MS 120420_11 NL: 6.23E5 m/z= 132.06420-132.06684 MS 120420_11 NL: 9.02E6 m/z= 116.06945-116.07177 MS 120420_11 NL: 8.85E4 m/z= 76.03855-76.04007 MS 120420_11 NL: 5.91E5 m/z= 176.10121-176.10473 MS 120420_11 NL: 1.25E6 m/z= 148.05895-148.06191 MS 120420_11 RT:17.50 - 21.00SM:5B 17.6 17.8 18.0 18.2 18.4 18.6 18.8 19.0 19.2 19.4 19.6 19.8 20.0 20.2 20.4 20.6 20.8 21.0 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e0 50 1000 50 100 NL: 5.01E6 m/z= 175.11720-175.12070 MS 120420_10 NL: 1.39E6 m/z= 133.09582-133.09848 MS 120420_10 NL: 9.62E5 m/z= 130.08496-130.08756 MS 120420_10 NL: 2.62E6 m/z= 147.11133-147.11427 MS 120420_10 NL: 2.80E4 m/z= 227.11160-227.11614 MS 120420_10 NL: 5.46E4 m/z= 241.12711-241.13193 MS 120420_10 Tau Phe Leu Ile Tyr Met Val Thr Ser Ala _Sar b-Ala Hyp Pro Gly Cit Glu Arg Orn Pip Lys Car Ans

7.5 14.5 min 13.5 17.5 min 17.5 21.0 min

RT:12.0 - 20.0SM:5B 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 18.0 18.5 19.0 19.5 20.0 Time (min) 0 50 1000 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e 0 50 1000 50 1000 50 100 NL: 3.66E7 m/z= 171.16725-171.17067 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 8.84E6 m/z= 207.13979-207.14393 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.84E6 m/z= 221.15530-221.15972 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.79E6 m/z= 235.17081-235.17551 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.93E6 m/z= 255.22393-255.22903 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.85E6 m/z= 263.20184-263.20710 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 8.77E5 m/z= 291.23286-291.23868 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 3.91E5 m/z= 319.26388-319.27026 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 C0 C2 C3 C4 C5 C6 C8 C10

Labelled ISTD acylcarnitines spiked in plasma extract

Quantitative amino acid & acylcarnitine analysis in plasma using

HILIC coupled to an Exactive Plus high resolution mass spectrometer

0 100 200 300 400 500 600 700 800 900 1000 0 200 400 600 800 1000 Alanine Hilic-Exactive plus MS Alanine Biochrom LC-Fluorescence

Passing & Bablok Fit

Identity

Passing & Bablok (I) fit (-21.28 + 1.19x)

(15)

For Research Use Only. Not for use in Diagnostic Procedures RT:7.50 - 14.00SM:5B 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e0 50 1000 50 1000 50 100 NL: 1.88E6 m/z= 126.02123-126.02375 MS 120420_11 NL: 4.24E6 m/z= 166.08517-166.08849 MS 120420_11 NL: 3.91E6 m/z= 132.10059-132.10323 MS 120420_11 NL: 1.28E6 m/z= 182.07935-182.08299 MS 120420_11 NL: 8.85E4 m/z= 150.05683-150.05983 MS 120420_11 NL: 1.80E6 m/z= 118.08508-118.08744 MS 120420_11 NL: 2.56E5 m/z= 120.06432-120.06672 MS 120420_11 RT:13.50 - 17.50SM:5B 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e 0 50 1000 50 1000 50 100 NL: 1.64E5 m/z= 106.04881-106.05093 MS 120420_11 NL: 9.98E5 m/z= 90.05406-90.05586 MS 120420_11 NL: 6.23E5 m/z= 132.06420-132.06684 MS 120420_11 NL: 9.02E6 m/z= 116.06945-116.07177 MS 120420_11 NL: 8.85E4 m/z= 76.03855-76.04007 MS 120420_11 NL: 5.91E5 m/z= 176.10121-176.10473 MS 120420_11 NL: 1.25E6 m/z= 148.05895-148.06191 MS 120420_11 RT:17.50 - 21.00SM:5B 17.6 17.8 18.0 18.2 18.4 18.6 18.8 19.0 19.2 19.4 19.6 19.8 20.0 20.2 20.4 20.6 20.8 21.0 Time (min) 0 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e0 50 1000 50 100 NL: 5.01E6 m/z= 175.11720-175.12070 MS 120420_10 NL: 1.39E6 m/z= 133.09582-133.09848 MS 120420_10 NL: 9.62E5 m/z= 130.08496-130.08756 MS 120420_10 NL: 2.62E6 m/z= 147.11133-147.11427 MS 120420_10 NL: 2.80E4 m/z= 227.11160-227.11614 MS 120420_10 NL: 5.46E4 m/z= 241.12711-241.13193 MS 120420_10 Tau Phe Leu Ile Tyr Met Val Thr Ser Ala _Sar b-Ala Hyp Pro Gly Cit Glu Arg Orn Pip Lys Car Ans

7.5 14.5 min 13.5 17.5 min 17.5 21.0 min

Quantitative amino acid & acylcarnitine analysis in plasma using

HILIC coupled to an Exactive Plus high resolution mass spectrometer

Thursday Poster

Number 423

RT:12.0 - 20.0SM:5B 0 50 1000 50 1000 50 1000 50 1000 50 100 R e la ti v e A b u n d a n c e 0 50 1000 50 1000 50 100 NL: 3.66E7 m/z= 171.16725-171.17067 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 8.84E6 m/z= 207.13979-207.14393 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.84E6 m/z= 221.15530-221.15972 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.79E6 m/z= 235.17081-235.17551 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.93E6 m/z= 255.22393-255.22903 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 1.85E6 m/z= 263.20184-263.20710 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 8.77E5 m/z= 291.23286-291.23868 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 NL: 3.91E5 m/z= 319.26388-319.27026 F: FTMS + p ESI Full ms [50.00-750.00] MS 120418_15 C0 C2 C3 C4 C5 C6 C8 C10

Labelled ISTD acylcarnitines spiked in a plasma extract

(16)

Criteria for evaluation

1.

2.

accuracy and precision of mass determination

3.

4.

(17)

494.25 494.26 494.27 494.28 494.29

m/z

0 50 100

R

e

la

ti

v

e

A

b

u

n

d

a

n

c

e

494.26876

494.26760

Mass distribution at the LLOQ (plain) and ULOQ (dashed)

in plasma (dynamic range of 1,000) with the Exactive Plus MS

2 ppm

10 ng/mL

(18)

[°C]

Time [days]

20 21 22 23 24 25 60 min

0

7

14

21

28

35

42

49

56

Temperature at the MS position depends on the

Air-Conditioning flow strength and

Additional room ventilation system

Temperature variability in our MS

research labs

[°F]

AC Room Temp.

at the MS location

19

20

21

22

23

24

25

26

66

68

70

72

73

75

77

79

= 3-5 [°C]

= 5-9 [°F]

(19)

20

21

22

23

24

25

26

27

28

29

0 6 12 18 24 30 36 42 48

Time [hours]

- 1.0

- 0.5

0.0

0.5

1.0

1.5

2.0

Mass Accuracy of caffein

[ppm]

Room temp.

Exactive MS temp.

Room Temp.

[°C]

Mass Accuracy on the Exactive HR-MS

and temperature fluctuation

External Calibration:

(20)

For Research Use Only. Not for use in Diagnostic Procedures 21.0 21.5 22.0 22.5 23.0 23.5 24.0 24.5 25.0 25.5 -5 -4 -3 -2 -1

0

1 2 3 4 5 0 7 14 21 28 35 42 49 56 calibration

Mass accuracy

[ppm]

Room Temp

[°C]

calibration

Mass Accuracy on the Exactive Plus HR-MS:

how we have worked ?

Exactive plusTemp

[°C]

25.5 26.0 26.5 27.0 27.5 28.0 28.5 29.0 29.5 30.0

Time [days]

1. Check the mass accuracy with

mobile phase « contaminants »

•

Si(CH₃)₂O))₆, m/z = 445.12003 • C₂₄H₃₈O₄, m/z = 391.28429

2. Re-calibrate if mass accuracy is

> 4 or 5 ppm.

3. Possibly, use lock mass with

these « contaminants »

(21)

Criteria for evaluation

1.

2.

3.

4.

quantification performed with our TQ-MS analyses

(22)

µg/L

Sirolimus

0 10 20 30 40 50 A re a R a ti o

Ciclosporine A

0 100 200 300 400 500 600 700 800 900

µg/L

A re a R a ti o

LC-ESI TQ discovery - MS

LC-ESI Exactive - MS

Dasatinib

0 100 200 300 400 500

µg/L

A re a R a ti o

Imatinib

0 2000 4000 6000 8000 10000

µg/L

A re a R a ti o

Fluconazole

0 10 20 30 40 50

µg/L

A re a R a ti o

Posaconazole

0 2 4 6 8 10

µg/L

A re a R a ti o

Calibration Curves of LC- Exactive-MS and LC-TQ-MS

(23)

Calibration Curves in plasma extract

analysed by LC Exactive Plus MS

0 2,000 4,000 6,000 8,000 10,000

ng/mL

0 5 10 15 A re a R a ti o 20 25

Imatinib : 10 – 10,000 ng/mL

nM

0 50 100 150 0.0 0.2 0.4 0.6 0.8 1.0 A re a R a ti o

25-OH-Vitamin D3 : 10 – 170 nM

(24)

Criteria for evaluation

1.

2.

3.

4.

(25)

4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 4.5 5.5 6.5 7.5 8.5

HR-MS

(HR-FS)

Passing & Bablok (I) fit 1.09 + 0.79x

Everolimus

Identity 2 4 6 8 10 12 14 2 4 6 8 10 12 14 Identity

Passing & Bablok (I) fit -1.93 + 1.18x

Tacrolimus

HR-MS

(HR-FS) 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16 -0.21 + 1.04x

HR-MS

(HR-FS)

Sirolimus

Passing & Bablok (I) fit Identity 0 50 100 150 200 250 0 50 100 150 200 250 - 5.11 + 0.97x

HR-MS

(HR-FS)

TQ-MS (SRM)

Ciclosporine A

Passing & Bablok (I) fit Identity

TQ-MS (SRM)

Passing & Bablok Fit of

immunosupressive drugs

in serum:

SRM versus HR-FS acquisition (N=100)

(26)

For Research Use Only. Not for use in Diagnostic Procedures 10 20 30 40 50 60 70 80 90 100 10 30 50 70 90

25-OH-vitamine D3

in plasma :

Identity

Passing & Bablok (I) fit

(0.63 + 1.04x)

25-OH-vitamin D3

[nM]

Determined by

LC-Exactive plus

MS

25-OH-vitamine D3

[nM]

(27)

0 500 1,000 1,500 2,000 2,500 3,000 0 500 1,000 1,500 2,000 2,500 3,000

HR-MS

[ng/ml]

TQ-MS

[ng/ml]

imatinib

in plasma:

Identity

Passing & Bablok (I) fit

1.0851x 1 78.412

R2 = 0.9808

Exactive plus

Exactive

(28)

Criteria for evaluation

1.

2.

3.

4.

level accuracy of Cs, QCs and UNK samples in comparison to

the quantification performed with our TQ-MS analyses

(29)

Ease of use in a clinical research environment

User friendly for lab techs

Easy follow up of mass accuracy status by mass deviation of contaminant ions

Si(CH

₃

)

₂

O))

₆

at m/z = 445.120025

C

₂₄

H

₃₈

O

₄

at m/z = 391.28429

Work with fast PCs

Handle Go of data: processing and storage

Are there bottlenecks for a shift of technology in Quan analyses ?

cost difference between TQ-MS and HR-MS

no need of Qual analyses

no HR specific guidelines by Authorities

(30)

The Goal of our work

Is Exactive Plus HR-MS able to perform robust quantitative

analyses

in a busy and productive clinical research lab ?

Quan

analyses by HR-FS :

Qual

analyses by HR-FS :

in comparison to TQ-MS

better « picture » of the samples : troubleshooting, adducts, charge states ...

time saving

identification of unknowns

fate of the analyte

in vivo :

e.g. drug metabolite profiles in samples

(31)

0

50

100

150

200

250

300

350

400

450

500

Patient #1

Patient # 2

3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 Time [min]

Parent Drug : imatinib M1 hydroxy-deacetyl-imatinib M2 demethyl-imatinib M3 demethyl-ketone-imatinib M4 demethyl-hydroxy/N-oxide-imatinib M5 hydroxy-desaturated-imatinib M6 hydroxy/N-oxide-imatinib M7 demethyl-carboxilic-imatinib M8 demethyl-glucuronide-imatinib M9 glucuronide-imatinib M10 hydroxy-glucuronide-imatinib m/z= 494.26629 A: 2x107 m/z= 468.25064 A: 1x104 m/z= 480.25064 A: 2x106 m/z= 494.22990 A: 5x105 m/z= 496.24555 A: 8x104 m/z= 508.24555 A: 4x105 m/z= 510.26120 A: 4x105 m/z= 524.24046 A: 4x104 m/z= 656.28272 A: 2x105 m/z= 670.29837 A: 3x105 m/z= 686.29329 A: 6x104

Profiling imatinib metabolites in parallel to

imatinib quantification in donor plasma

Relative metabolite amounts

(32)

Quan

Qual

Targeted quantitative analysis

• therapeutic drug research

• biomarker research

Validated

metabotyping (*)

Relative quantification of

• lipid profiles

• drug metabolite profiles

• etc

M

e

ta

b

o

lo

m

ic

s

Metabotype (*)

Discovery

Fundamental + metabolomics

Metabotype (*)

Validation

Identification of unknowns;

biochemical explanation, etc.

Quan or

Quan/Qual analyses

using LC-HR-FS acquisition

interpretation

sample stratification

Personalized medicine

research

Semiquantitative Determination of Metabotypes using HR-MS :

a Fundamental Step Forward in Clinical Research Analyses

(33)

The LC-MS analyses that we performed in HR-FS acquisition mode with the Exactive and

Exactive Plus MS, showed that :

HR analysis is as specific as SRM analysis (R

≥

25,000 at all analyte m/z)

HR analysis is compatible with usual plasma extraction (PP, SPE and SLE)

Exactive Plus MS is compatible with a clinical research labs needs

HR-FS acquisition mode allows simultaneous Qual

analyses that should have a strong

impact in clinical research such as the semi-quantitative determination of metabotypes

Conclusion and Summary

(34)

Acknowledgements

Maciej Bromirski, Olaf Scheibner, Sara Robinson,

Bénédicte Duretz and Subodh Nimkar

Emmanuel Kottelat, René Nellen and Hamid Sobhi

Hugues Henry, Steve Bruce and Alexandre Béguin

Thermo Fisher Scientific, Bremen, Paris, San Jose

Quantitative Mass Spectrometry Facility, CHUV