ffiYT#Yffiffiru'A Breakthrough in Tissue Engineering

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Cell5ignaliingTransmembrane Potenlial (TMP) is a rryell known cellular signaling pathway ihar regulaies the synthesis of variousproteins at the appropriate time in living cells. Many non-communicable illnesses like cancer, heart diseases anddegenerative disorders like cartilage loss and different kinds of inflammation are also linked to disturbances in iheprotein transcripiion process (Cone CD, Variation of Transmembrane Potential as a basic mechanism of miiosisconirol: Oncology,24:438-470, 1970).li was ihought during the last felnr decades that if an appropriate merhodcould be developed to alterTMP in a controiled manner, most of these disorders that are prciern linked could becorrected. The ion pump in the membrane activaies the normal cellular channels for active synrhesis and geneexpression of appropriate proteins in different groups for a specific function. For instance the HSP grouppredomrnantly encourages tissue regeneraiion and can be useful in many chronic degenerative disorders, whereasthe p53 group controls cell growth, thus playing an imporlant role in arresiing mitosis, thereby finding applicationin treating malignant neoplastic disorders. The p53 tumour suppressor gene stops the formation of tumours by itsactivities. lf a person inherits only a copy of p53 gene from their parents, they are predlsposed to cancer and usuallydevelop several independent tumours in a variety of tissues in early adulthood (rare condition known as Li-FraumeniSyndrome). Mutation in p53 is found in most tumour types and contributes to the complex network of molecularevents leading to tumour formation. The p53 gene has been mapped to Chromomsome I7. ln the cell, the p53protein binds to the DNA, which in turn stimulates another gene to produce a protein called p21 which interacr-with a cell- division- stimulating protein (CDK2). When p21 complexes with CDK2 the cell can not pass through to tl,*next stage of cell division. When the p53 is mutated or fails to express, it can no longer bind to the DNA and as aconsequence the p21 protein is not made available to act as the stop signal for cell division, thus the cell dividesuncontrollably and forms tumours.

Tissue engineering is a field of science which involves altering, modi{ying and inducing controlled regeneration anddegeneration in biological tissues. One of the methods of engineering the tissues is by altering the iignalingpathways. These pathways can be altered by various intercellular parameters such as TMP, signal transduction(ligand, receptors, and signal propagation), cell cycle check points, telomere metabolism, RNA inter-ference, etc.

Rotational Field Quantum Magnetic Resonance therapy orQMRT" is a functional method of altering one of the mostprominent intercellular pathways i.e. the TMP pathways. lt is hypothesized over the last24 years of research thatcontrolled altering of the TMP by application of specifically modulated radio frequency signals in the presence of ahigh instantaneous magnetic field can bring about changes relating to pro-apoptotic protein groups in the tumourcells. lt is known that chromosomes, following the cell signaling received as a result of variation of potentia[ (-70 to-90 mV in healthy cells, -40 to -60 mV when infected, -20 to -30 mV in neoplasticEells, 0 mV when the cell dies) in thecytoplasmic membrane, activate the emission of messages by the genes that regulate cell dynamics for normal cellfunction or for mitochondrial activities for ATP production, through electromechanical resonance (also called stressresponsive).

The delivered, instantaneous mode, wide spectrum magnetic andRF modulations are highly cell and site specific. This is based onthe proton density of the tumour tissue, the permittivity,permeability of the tumour site, and depth of penetration fromskin to target tissue.

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Malignant NeoPlastic DisordersMalignant neoplastic disorder commonly known as cancer, is a chronic debilitating disease with genetic and

environmental aetiology. lt is predicted that there will be an increase in cancer incidence worldwide, with about 15

million new cases diagnosed annually. Currently available treatment modalities for cancer (surgery, chemotherapy,

radiation therapy or hormonal therapy) are known for their side effects and invasive nature, despite their benefits.

Thus the need for new treatments and palliative care modalities that can not only arrest tumour.progression without

the commonly experienced adverse effects, but can also help improve quality of life'

Tissue Engineering in Malignant Neoplastlc Disordersp eMRT beams when appropriately controlled and modulated can alter the TMP to stimulate specific groups of

proteins, thus initiating one or more signaling processes' '.D Studies have shown that Nuclear Magnetic Resonance (NMR) exposure sensitizes tumour cells to apoptosis.

(Ghibelli L, cerella c, cordisco s, et al: NMR Exposure Sensitizes Tumour cells to Apoptosis' Apoptosis 1 i: 359-

365,2006)

D lt is hypothesized that expression of p53 group of proteins is achieved by precisely altering the TMP pathway'

This drives the tumour cells to apoptose.

p The cells continue to live in a quiescent state (vegetative form of life) until it finally attains apoptosis and are

recycled by the bodY.

Clinical Efficacy of QMRT' in Neoplastic disordersCYTOTRON6- eMRTs is a new modality for managing Neoplastic disorders with no known adverse effects. lt is an

emerging, stand-alone, adjuvant or neo- adjuvant therapy, poised to fill the unmet medical needs in terminally ill or

advanced cancer patients. The treatment method involves exposure of the tumour site to the modulated radio

signals generated by the Cytotron". Each exposure lasts for about 60 minutes for 28 consecutive days. Special

MRI-pD sequence is performed for precise dosimetry. A diagnostic MRI is required to evaluate the lesion status based

on the Response Evaluation Criteria in Solid Tumours (RECIST v1.0) and the tumour's metastatic profile pre and post

therapy.

ln a clinical investigation carried out on 98 patients with histopathological confirmation of solid tumour, declared

terminally ill or unwilling to undergo standard of care therapies, significant clinical outcomes were observed.

Extension of life was determined by comparing predicted survivat derived from a Palliative Prognostic Score (PaP5)

model with actual survival. The qualiry of life (QOL) was recorded using the Functional Assessment for Cancer

Therapy- General Populatign (FACf-GP) questionnaire and Karnofsky Performance Status (KPS) scores. Tumour

status, pre- and post-treatment was evaluated using MRI/PET-CT. The patient follow up was for 12 months, with

quarterly assessments, with periodic follow up and survival updates until close of the study. Paired 't' test as

t lmproves quality of life in patients .. ',

p Relieves severe to exkemely severe pain ,

I Enables tapering of pwerful pain killers and opiates like morphine, etc,.].> lmproves qppetite and weight gain, enhances social life, eh

o Extends life expectancy

r Very likely aids in stabililng the d'rsease by anesting fumour progrexion

> V6ry likely prevents fumour metaslasis

p No known adverse effecb

> '\4hole body treatrnen[ multiple trmoursites can be exposed

simultaneously

> QMRT@ is noninvasive, non:lhermal and nonionizing

D Twenty-eight mnsecutive exposures of one hour daily

D Patients generally require no hospitalization

> The device can also be installed in daycare centers with appropriate

facilities

p The device is self-shielded and does not require shielding of the

trcatflent room

r Fully-automatic dosimetry, requidng minimal baining fortechnologist and

specialist

> Noconsumablesnecessary

applicable io dependeni samples uras applied for analysing KPS score and FACT-GP scores at completion of and onemonth after completion of therapy. Level of significance was set at p<0.05. However, exaci significance is annotatedin the tables presenting the outcome of analysis.

Results and Outcome**Patient Cohort: A total of 98 patients were assigned to the study after screening. There were 55 (56.,1%) female and43 (43.90io) ma le patients. The mean age was 54.5 + I 3.7 years, with ages ranging from l 5 to 84 years. Out of therecruited patients, 86 (male 44c/o,female 56 o/o) completed the twenty-eight days exposure as per protocol.

Primary Outcome: Thirty-one patients were still alive at the end of the study period of 4 years. Comparing predictedsurvival intervals with actual life expectancy during the follow up, there was a significant increase in life expectancyfrom the predicted mean of 117+46 days to the actual mean of 377+307.days, (t = - 8.21, p= 2.13 E-12).

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Patient Survival- Predicted vs. Actual n = 8680

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Secondary Outcome: Significant improvement in Karnofsky Performance Status and FACT- Gp scores. (Table 2)

' valws in neu x sa; t Kdhotsky Peiqnw s@E: t F@cri@al Awsfrotil ol c@ nprapy- Gqwar popltari@, @ FAclT.dg

Status of tumour- post therapy

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' lncludes paliqls ftviewed beyond the fatbw up petiod ot 12 nonths.

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Conclusion> lmproves quality of life in patients by relieving pain, improving appetite and weiqht gain.

> Significant improvement in general quality of life.

a Significant extension in life expectancy

> Very likely aids in stabilizing the disease by arresting tumour progression.

This treatment can constitute a useful addition to standard of care therapy and may become a significant modality

in the care of cancer patients in clinical practice and a safe therapy even in terminally ill cancer patients.

Techn ical 5pecincation of C'/TOTROlti'

Classilication: Class lla Medical Device.

lndication of use: The Device is intended to be used for Regenerative and DegeneraUve

Tissue Engineering i.e. it can be used for regenerallng fisues in-silu and to cause

degeneration of unconfoiled gmlr,ih of tlssues.

Degeneration of lissues: The cunent indication is for use ifl potein linked abflormally

regenerating dlsorders like neoplastic disease enabling tjssu€ apoptosis and preventing

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golkaindications: Critically ill patients on life support system, Pregnancy, Patents unable

to lie down forthe duration of herapy, Patientswilh eiectricaily, magnetically ormechanically

aclivated implants. (e.9. Cardiac pacemakers, Bio stjmulators, Neuro stjmulators, Cochlear

implanls, Hearing aids)

MRI incompatible implants near the target region. e.g. lntra medullary nail, lntacranial

aneurysm clips, stents, Intra orbital metal fragments etc.

Patients with neoplastic disease where there is no targetable solid lesron e.g. Multiple

myeloma and Leukemia.

0ru9 interactions: The following group of drugs hat use lhe same o. similar cellular

patrmys as QMRTo may interact with he CYrOTRONo exposure, like Calcium Channel

Blocken and Proton Pump lnhibitors in cases o{ maligsant neoplastic disorder. Patients

should be advised to lake medicaiion with ditrerenl mode of acton.

Product Specifications

The power supply Cytotron must meet these spec.ifications:

a. Voitage fluctualiofl+/- 10% or less

b. Voltage imbalance tl 3% or less

c. Frequency variation +/- 4% or less

d. Voltage distortion'lliD = 10% or less

Recommended environmental specifi cationsOperating lemperature cnge 18'C to 30"C, Humidity raflge 10% to 75% RH, Atmospheric

pressure 700 to 1060 hPa.

Tnnsport / Storage Temperature range 10'C to 80'C, Humidity range 10% to 90% RN,

Abnospheric pressure 500 to 1060 hPa

Mode of usage: Conllnuous

Life of lhe equipment Typically assessed at about ten years

Typical operating vottage: 230 V 50 Hz, single phase

Maximum Operating cunent: l2Amps

Typical operating cunent 6A

IEC classification: Iype 8, Class 1, lPX0

ItlDo classification: Class lla

Iarget rssolution:'1'1.25 deglees

Power supply type: Medical grade switch mode power supply compllng with EN 60601-l ,

EN 60601-1-2

Frequency band: VLF, LF, HF and VHF radio bands

lnstantan€ous magnetic field strength: 1mT io 6T for the time duration 2.0psec tol0msec

depends on the featment and Dosimetry mlu€.

E-Field: Emadband; average 100 dB V/m/MHz @ 4MHz

H-Field: Broadband; 20dB (below'1 kHz)

Broadbafld commof, mode cunent in control cables: 1 00dBmlVMHz @ '150 kHz

Fuses: Mains Fuse-12A, lsolation Transformer Fuse-2.5A

Laser.Guiding System

Output 625 to 680 nanometer wave length less than 5 mjll watt, Complies with CFR Part

1 040.1 0 and 1040.11 Class lll A LASER applhation

QMRT Guns

Magnetic field

Type: MF6040-L

Guns: K- - Fenite type; Near Field; gain; 1 OdB

Typical Voltage: 60 Volts

Typical Cunenl 4Amps

Radio frequency

Type ofantenna: Hellcal

Q factorofhe antenoa: 560

Anlenna gain: 13 dB

Cenbe frequencf 68.4 MHz

3dBBw{Bandwidth): t4MHz6dB Bw(Bandwidth): t10 MHz

lnputimpedance: 50 OHM

lnput connector: SMA

Physical Dimension

Cytotron deYice dimensions:

Central control unit dimensions:

Coating:

Patieni rveight:

Patient b€d weight:Earthing clip w€ight:Palient transmissiotl system:(Acrylic Sh€et + Metal Frame)

Total bed saf. working load:

4500mm (L) x 1210mm (W) x 1600mm (H)

Weight approx. 1900 Kg'l600mm

{L) x 780mm (!U x 1455mm (H)

Weight approL 200 Kg

Powder coatjng/Paint and Lacquer coating

body for scratch prctecton and prevent from

conosion

Max. '157 Kg

12.95 Kg (Part No: SCL-A-o1-LB)

50 Gms (Pa.t No: SCL-A{2-EP)22Kg

170 Ki

Standard Applied: BS EN 980:2008, BS EN 104 1:2008, BS EN 623662008, IEC 60601 -'l,

IEC 60601-1-1, IEC 60601-1-2, IEC 62304, ISO 9001:2008, ISO 13485:2003, ISO

1497 1:2007, lS0 1415$1:2003, ISO 14155-2,2003.

Approvals: lS0 9001:2008, ISO 13485:2003

Accreditations: AJ,IAB, UMS, C|\4DCAS

Product Cedification: Annex ll of lrlD0 93/4ZEEC as Amended by 2007147|EC

'Owing ro conlinuour deveiopmen! spe<i6<ationJ are subje(tochange without notice.