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MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR
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MECHANISM OF MALIGNANCY BY DR BASHIR AHMED DAR ASSOCIATE PROFESSOR MEDICINE SOPORE KASHMIR

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Malignancy (from Latin male "badly" + -gnus "born") is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers …

Malignancy (from Latin male "badly" + -gnus "born") is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis.
Malignancy is most familiar as a characterization of cancer. A malignant tumor contrasts with a non-cancerous benign tumor in that a malignancy is not self-limited in its growth, is capable of invading into adjacent tissues, and may be capable of spreading to distant tissues. A benign tumor has none of those properties.

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  • 1. MALIGNANCYBY DR BASHIR AHMED DARASSOCIATE PROFESSOR MEDICINECHINKI PORA SOPOREKASHMIREmail –drbashir123@gmail.com
  • 2. MMMC Annual night
  • 3. MMMC Annual NightCarol-I will always love you
  • 4. The cell
  • 5. The cell• The cell contains nucleusand in the nucleus arechromosomes.
  • 6. ChromosomesChromosomes arethe rod-shaped, filamentousstructures, whichbecome visibleduring celldivision.
  • 7. Chromosomes• Chromosomes arecomposed of thinchromatin threads• Each chromatinthread in turn ismade of DNA.
  • 8. Chromosomes• A chromosome is about0.004 mm long• The DNA is about 4 cm long• This is about 10 000 timeslonger than thechromosome• So it has to twist like acorkscrew and coil to fitinside• If you unraveled thesecoils, youd have a six-footlong double strand ofdeoxyribonucleic acid-DNA.
  • 9. Chromosomes• DNA is wrapped tightlyaround histones andcoiled tightly to formchromosomes
  • 10. Chromosomes
  • 11. DNA• DNA is made of• Nucleotide = nitrogen base (purine orpyrimidine) + phosphate group + pentosesugar ( ribose or deoxyribose)• They are units of DNA.
  • 12. DNA NucleotideOO=P-OOPhosphateGroupNNitrogenous base(A, G, C, or T)CH2OC1C4C3 C25Sugar(deoxyribose)
  • 13. RNA• RNA is made of• Nucleoside= nitrogen base(purine orpyrimidine)+ pentose sugar(ribose), butwithout phosphate group• They are units of RNA.
  • 14. DNA• Nitrogenous base is in the centre andphosphate and sugar at the legs of ladder.• The ladder coils on itself to form double helixstructure.• Youve got six billion of these pairs ofnucleotides in each of your cells, and amongstthese six billion nucleotide pairs are roughly30,000 genes.
  • 15. DNA Double HelixNitrogenousBase (A,T,G or C)“Rungs of ladder”“Legs of ladder”Phosphate &Sugar Backbone
  • 16. Nitrogenous Bases• PURINES1. Adenine (A)2. Guanine (G)• PYRIMIDINES3. Thymine (T)4. Cytosine (C) T or CA or G
  • 17. Chargaff’s Rule• Adenine must pair with Thymine• Guanine must pair with Cytosine• Their amounts in a given DNA molecule will be aboutthe same.G CT A
  • 18. DNA Double HelixPPPOOO123455335PPPOOO12 3455353G CT A
  • 19. BASE-PAIRINGSCGH-bondsT A
  • 20. DNA DOUBLE HELIX
  • 21. GENES• Genes are segments of DNA which contain setof instructions that decide what the organismis like, how it survives, and how it behaves inits environment• Each persons DNA is different - this is whatmakes each of us unique.
  • 22. Genes• Genes are the means by which a cell producesproteins, each of which have a very specificrole.
  • 23. Genes• A mutated gene can cause overproduction ofa protein, underproduction of a protein, oralteration of a protein that may be unable tocarry out its purpose.
  • 24. Genes• Oncogenes typically produce more of theirprotein product when mutated, while tumorsuppressor genes typically produce less oftheir protein product when mutated.
  • 25. Your genes decide• Whether you are tall or not• The color of your hair• The color of your skin• Whether you are more likely to develop certaindiseases• Whether you are good at sports• How you respond to environmental triggers• What you look like inside and out• And so many other things
  • 26. Genetic Diversity…• Different arrangementsof NUCLEOTIDES in anucleic acid (DNA)provides the key toDIVERSITY among livingorganisms.
  • 27. Genes• The particular order of thebases is called the DNAsequence. The sequencegives the exact geneticinstructions needed tocreate a particular organismwith its own unique traits.
  • 28. Genes• Specific sequence of bases alsocarry the information needed forconstructing proteins.• These proteins are producedthrough process of transcription,translation etc
  • 29. Genes• Proteins provide the structuralcomponents of cells and tissues aswell as enzymes for essentialbiochemical reactions. The humangenome is estimated to be made ofmore than 30,000 genes.
  • 30. MUTATIONS• Loss of DNA• Gain of DNA• Changes in nucleotides• Epigenetic effects
  • 31. DAMAGE TO DNA OR MUTATIONS• Any change in DNAsequence of basepairs
  • 32. DAMAGE TO DNA OR MUTATIONSBecause of Deletions A deletion could be as small as a single base oras large as the gene itself.• .
  • 33. DAMAGE TO DNA OR MUTATIONSInsertions are mutations in which extrabase pairs are inserted into a new placein the DNA. Because of insertion
  • 34. DAMAGE TO DNA OR MUTATIONSA substitution is a mutation thatexchanges one base for another Or reciprocal translocation
  • 35. DAMAGE TO DNA OR MUTATIONSIn an inversion mutation, an entiresection of DNA is reversed. Because of inversion
  • 36. DAMAGE TO DNA OR MUTATIONS• Errors may occur duringreplication, transcription, or translation.
  • 37. MUTATIONS OR DAMAGE TO DNATerminalDeletionRingChromosomeRobertsonianTranslocationDeletion ReciprocaltranslocationIsochromosomesInsertion InversionDuplication
  • 38. MUTATIONS OR DAMAGE TO DNANucleotideDeletionsNucleotideInsertionsNucleotideSubstitutions
  • 39. DAMAGE TO DNA OR MUTATIONS• Before a cell divides, the DNA is checked to makesure it has replicated correctly. (If DNA does notcopy itself correctly, a gene mutation occurs.
  • 40. DAMAGE TO DNA OR MUTATIONS• A point mutation, or single basesubstitution, is a type of mutation that causesthe replacement of a single base nucleotidewith another nucleotide of the geneticmaterial, DNA or RNA. Often the term pointmutation also includes insertions or deletionsof a single base pair.• As was shown in previous slides.
  • 41. DAMAGE TO DNA OR MUTATIONS• Point mutations that occur in non-codingsequences are most often withoutconsequences, although there are exceptions.
  • 42. DAMAGE TO DNA OR MUTATIONS• If the mutated base pair is in the promotersequence of a gene, then the expression ofthe gene may change.
  • 43. DAMAGE TO DNA OR MUTATIONS• An organisms DNA affects how it looks, how itbehaves, and its physiology for exampledivision of cells , growth etc. So a change in anorganisms DNA can cause changes in allaspects of its life.• Your DNA contains a set of instructions for"building" a human. These instructions areinscribed in the structure of the DNA moleculethrough a genetic code.
  • 44. DAMAGE TO DNA OR MUTATIONS• The sequence of these bases encodesinstructions. Some parts of your DNA arecontrol centers for turning genes on andoff, some parts have no function, and someparts have a function that we dontunderstand yet. Other parts of your DNA aregenes that carry the instructions for makingproteins — which are long chains of aminoacids. These proteins help build an organism.
  • 45. DAMAGE TO DNA OR MUTATIONS• Somatic mutations occur in non-reproductivecells and wont be passed onto offspring.• The only mutations that matter to large-scaleevolution are those that can be passed on tooffspring. These occur in reproductive cellslike eggs and sperm and are called germ linemutations.
  • 46. DAMAGE TO DNA OR MUTATIONS• There are many types of mutations thatchange not the protein itself but where andhow much of a protein is made. These typesof changes in DNA can result in proteins beingmade at the wrong time or in the wrong celltype. Changes can also occur that result in toomuch or too little of the protein being made.
  • 47. Carcinogen or Mutagen• A carcinogen ormutagen is anysubstance or agentthat, damages oralters cell DNA.
  • 48. Carcinogen or Mutagen• A carcinogens may bethe initiator — theagent that alters ordamages DNA, thebasic coding systemof cells.• They may also bepromoters —encouraging out-of-control cell growth
  • 49. Carcinogen or MutagenHuman viral pathogens• Oncogenic RNAViruses, Oncogenic DNAViruses• Retroviruses (HIV)• Epstein-Barr viruses• Herpesviruses-HSV-2• HBV• Papovaviruses• Adenoviruses
  • 50. Carcinogen or Mutagen• Ionizing radiation• UV from the sun andtanning lamps• X-rays: medical and dental• Radon, cosmic rays, andgamma radiation
  • 51. Carcinogen or Mutagen• Solar UV radiation is associated with skincancers – squamous CA, basal cellCA, malignant melanoma, air-skinned andelderly are susceptible
  • 52. Carcinogen or Mutagen• Earlier use of X-rays caused skincancer, leukemia and papillary thyroid CA• Radiotherapy causes radiation-inducedmalignancy 10-30 yrs later – usually sarcomas• Diagnostic X-rays are considered to have noincreased risk except in abdominal x-rayswhich increase incidence of leukemia in thefetus.
  • 53. Carcinogen or Mutagen• Radioisotopes• Osteosarcoma common among factory workerswho use radium-containing paints• Radioactive mineral mining in Europe and USAassociated with lung cancer• Thorium increases risk of liver cancer –hepatocellular, angiosarcoma, cholangiocarcinoma• Radioactive iodine – increased risk of cancer 15-25 years later.
  • 54. Carcinogen or Mutagen• Nuclear Fallout• Hiroshima, Nagasaki (atomic blasts), Marshallislands (atmospheric testing of nuclear devicecontaining radioactiveiodine), Chernobyl, 1986.
  • 55. Carcinogen or Mutagen• Nutritional deficiency (having antioxidant effect)• Protein deficiency• Carotenes and retinoid - deficiency• Tocopherols - deficiency• Selenium (glutathione peroxidase) - deficiency• Zinc deficiency• Flavanoids (enzyme inhibition) - deficiency• Vit C deficiency• Vit E deficiency• High fat• Low-fiber diet and colonic CA• Fatty diet with breast ca• Betel leaves with oral ca
  • 56. Carcinogen or Mutagen• Industrial chemicals• Exposure to pesticides• Agricultural chemicals• Asbestos• vinyl chloride• benzene• Hydrocarbons in cigarette smoke• Aflatoxin: fungal product• Nitrosamines and amidesConverted to nitrites by gutbacteria• food preservatives• food dyes
  • 57. Carcinogen or Mutagen• Aromatic amines and azodyes• Polycyclic aromatichydrocarbons• Tobacco smoke• benzene• carbon tetrachloride• vinyl chloride• asbestos fibers• pesticides• dioxins
  • 58. Carcinogen or Mutagen• Carcinogenic substances may be inhaled, absorbedthrough the skin or even ingested in some cases. Effectof carcinogenic chemicals used in industrial processesis felt beyond the workplace• Often water is contaminated and air is polluted bycarcinogens, causing additional cancers in surroundingcommunities.• The idea of carcinogens (in soot)was first put forwardin 1775 as doctors discovered a high incidence ofscrotal cancer among chimney sweeps in uk.
  • 59. Carcinogen or Mutagen
  • 60. Carcinogen or Mutagen• Hormonal Oncogenesis & drugs (promotors)• Promoters enhance proliferation of initiated cells. Expandpopulation of initiated cells• Increase risk of additional mutations (during DNA synthesis)• Oral Contraceptives• Estrogens/ Progesterones/Androgens• prolactin, thyroxin• Phenobarbital• Estrogen – breast ca,enodmetrial hyperplasia ->endometrial cancer• Diethylstilbestrol (DES) – vaginal and uterine ca
  • 61. Carcinogen or Mutagen• Breakdowns in immunity• Healthy immune system can target and destroycancer cells. When cancer cells have alteredproteins at its surface, cells are not destroyed.Risk of cancer increases With age.• HIV infection• Immunosuppressant drugs• Anxiety and depression
  • 62. Carcinogen or Mutagen• Inflammation like• Chronic hepatitis -> hepatocellular carcinoma• Colitis -> colon cancer• Osteomyelitis sinus tracts -> squamous cancer• Chronic bronchitis -> lung cancer
  • 63. Carcinogen or Mutagen• Genetic Oncogenesis (Role of Inheritance)• Association with inherited diseases,MendelianInheritance, Dominant or Recessive.• Examples• Retinoblastoma• Wilm’s tumor• Neurofibromatosis (type 1 von Recklinghausen’s disease)• Multiple endocrine adenomatosis (MEN)• Familial polyposis coli• Nevoid basal cell carcinoma syndrome• Syndromes of immunodeficiency
  • 64. Carcinogen or Mutagen• Besides• O2 free radicals DNAdamage• Foreign bodies
  • 65. Normal Cell/Mutated CellDNA of a normal cell DNA of mutated cell
  • 66. Damage to p53 gene• When DNA is damaged there might also occurdamage to p53 gene. Due to damage to p53gene the DNA repair protein gets inactivatedand there fore does not repair DNA.
  • 67. Damage to p53 gene• p53 gene damage also leads to inhibition ofapoptosis. So that damaged cell if not repairedwould get killed and destroyed by immunesystem & killer cells had there been nodamage to p53 gene.
  • 68. APOPTOSISProgrammed cell deathOrderly & normal cellular self destruction
  • 69. APOPTOSIS: important in embryogenesisMorphogenesis (eliminates excess cells):Selection (eliminates non-functional cells):
  • 70. APOPTOSIS: important in embryogenesisImmunity (eliminates dangerous cells):Self antigenrecognizing cellOrgan size (eliminates excess cells):
  • 71. APOPTOSIS: important in adultsMaintains organ size and function:Apoptosis+ cell divisionCells lost by apoptosis are replaced by cell divisionX
  • 72. APOPTOSIS: Role in DiseaseTOO MUCH: Tissue atrophyTOO LITTLE: HyperplasiaNeurodegenerationThin skinetcCancerAthersclerosisetc
  • 73. APOPTOSIS: Role in DiseaseCancerMost cancer cells are defective in apoptotic response(damaged, mutant cells survive)High levels of anti-apoptotic proteinsorLow levels of pro-apoptotic proteins===> CANCER
  • 74. Immune Surveillance System• Apoptosis normally eliminates aged and damagedcells or excess cells that are not needed throughdifferent mechanisms e.g through immunesurveillance system as follows• through• 1) Natural killer (NK) cells• 2) Cytotoxic T-cells
  • 75. Immune Surveillance System• 3) B-cells :• Tumor associated antigens stimulateproduction of specific antibodies by host B-cells• These specific antibodies bind together ontumor cell surface leading to destruction oftumor through cytotoxic T-cells that kill IgG-coated tumor cells
  • 76. Immune Surveillance System• Healthy immune system would target anddestroy mutated cells. But the mutated cellshave developed altered proteins at their cellsurfaces,neoantigens & tumor-associatedantigens. Therefore escape recognition anddestruction by immune system.(Failure ofImmune Surveillance)
  • 77. Immune Surveillance System• Risk of cancer increases: With age When animmune system has been suppressed for along time , HIV infection, Immunosuppressantdrugs. Anxiety and depression
  • 78. Mechanisms by which tumor escape immune defenses:1) Reduced levels or absence of MHCI molecule on tumor sothat they can not be recognized by CTLs2) Some tumors stop expressing the antigensThese tumors are called “antigen loss variants”3) Production of immunosuppressive factors by tumor e.g.transforming growth factor (TGF-β)4) Tumor antigens may induce specific immunologic tolerance
  • 79. 5) Tumor cells have an inherent defect in antigenprocessing and presentation6) Blocking of receptors on T-cells by specific antigenantibodies complex (after shedding of tumor Ag)prevents them from recognizing and attacking tumorcells7) Antigens on the surface of tumors may be masked bysialic acid-containing mucopolysaccharides8) Immune suppression of the host as in transplantpatients who show a higher incidence of malignancy
  • 80. 2. Normal Chemical Signals tell Normal cellwhen to start and stop dividing.
  • 81. Damage to p53 gene• Two genes involved in apoptosis are the tumorsuppressor gene p53 and the bcl-2 protooncogene.• Tumor-suppressor genes p53, function likebrakes, keep cell numbers in check .
  • 82. Control of the Cell Cycle• Cell division or Mitosis goes through severalstages such as• Prophase• Metaphase• Anaphase• Telophase• and Cytokinesis
  • 83. Control of the Cell Cycle• Then the cell enters Interphase, which is anintervening stage at which the cell preparesfor the next cell division or goes into restingphase where the cells undergo differentiationto specific cell type.
  • 84. Control of the Cell Cycle• Interphase consists of sub-stages such as G1, Sand G2; where, G stands for the gap inknowledge
  • 85. Control of the Cell Cycle• The G1 phase is----preparatory phase for DNAreplication.• The S-phase is for DNA replication and repair ifneeded• and G2 stage is a preparatory phase for M-phase(Mitosis)
  • 86. Cell cycle checkpoints• The major checkpoints lie in between G1 andS phase and G2 and M-phase and anothercontrol point exists within the M-phase eventsat anaphase.
  • 87. Cell cycle checkpoints• Cell cycle checkpoints are biochemicalsignaling pathways that sense damage to theDNA structure or impaired chromosomefunction and elicit complex cellular repairresponses.
  • 88. Cell cycle checkpoints• These checkpoints rapidly induce cell cycledelay, generally at the G1, S, and G2checkpoints, allowing time for the activationof DNA repair mechanisms.
  • 89. Cell cycle checkpoints• The checkpoints also maintain cell cycle arrestwhile the repair takes place and initiate cellcycle progression once repair is complete . Ifthe DNA cannot be repaired adequately, thecell then undergoes permanent cell cyclearrest and apoptosis.
  • 90. Function of check points• Can DNA synthesis begin?• Has DNA synthesis been completed correctly?And go for mitosis• Are all chromosomes attached to spindle?• Can sister chromatids separate correctly?
  • 91. Function of check points• Damage to p53 also causes disturbance inproof reading of DNA prior to replication at G1phase of mitosis.(failure at check point)• Cancer cells lose normal restraints forreplication of damaged DNA and G1/Sprogression of cells with damaged DNA
  • 92. Function of check points• If cell receives “GO” signal, it divides• By Internal signals: cell growth (size), cellnutrition• By external signals: “growth factors”• If cell does not receive signal, it exits cycle &switches to G0 phase, non-dividing, workingstate
  • 93. Control of the Cell CycleOther mechanisms for controlling progressthrough the cell cycle areLength of TelomeresChemical Signals from within and outsidethe cell
  • 94. Chemical Signals that Control the Cell Cycle1. Cyclin and Kinase-proteins that initiate mitosis-requires buildup of cyclin to pair with kinase2. Hormones-chemical signals from specialized glandsthat stimulate mitosis3. Growth Factors-chemical factors produced locally that stimulatemitosis
  • 95. Failure to Stop atCell Cycle CheckpointsMutation in a gene thatusually slows the cellcycleRate of cell division isaccelerated.Failure to pause forDNA repairFaulty DNA leads tounregulated cell growth.Loss of control overtelomere lengthCancer cells havetelomerase, an enzymethat elongates telomeres.Cells continue to divideafter 50 mitoses.
  • 96. Control of the Cell Cycle• Incorrectly repaired DNA, however, continuesto replicate, leading to accumulation of themutation and, thus, elevated cancer risk.Studies have shown that mutations in cellcycle control genes, such as p53 and p21, aredirectly linked to chromosomal aberrationsand genomic instability
  • 97. Control of the Cell Cycle• Mutation is thus passed on to daughter cellsthat results in Successive accumulation ofmutations.
  • 98. 1st & 2nd Mutations• The genetically alteredcells have, over time,reproduced unchecked,crowding out thesurrounding normalcells. The growth maycontain one million cellsand be the size of apinhead. At this pointthe cells continue tolook the same as thesurrounding healthycells.
  • 99. Contact Inhibition: (density-dependentinhibition of growth)• Two or more normal cells come in contactwith each other, they tend to stop dividingand form a single layer or sheet of cells calleda confluent monolayer.• Cancer cells will continue to grow and pile upon top of each other even after forming themonolayer.
  • 100. • Normally cells attach to each other by variouscell junctions so that they are fixed in place• Communicate with each other via GrowthFactors• But all such things are lost when cell ismutated.• In other words cells Escape Regulations.
  • 101. • Cancer cells do not respond to crowding; lossof contact inhibition• Leads to a disorganized mass
  • 102. Interaction of a Cell at Riskwith a Carcinogen Can Producean Initiated Cell• An initiated cell is the first step information of a tumor• For an initiated cell to become atumor both the Promotion andProgression stages have to occur• The larger the number of initiatedcells the higher the breast cancerriskCellsatRisk
  • 103. Initiation Promotion Progression•Mutation•Cancer Gene•Proliferation•Independence•Mutation•Invade & SpreadStages of Cancer FormationUnspecializedCellInitiatedCellBenignTumorMalignantTumorLatency Period, 20 years or more
  • 104. Third mutation• Not all mutations that lead to cancerous cells result in the cellsreproducing at a faster, more uncontrolled rate. For example, amutation may simply cause a cell to keep from self-destructing.All normal cells have surveillance mechanisms that look fordamage or for problems with their own control systems. If suchproblems are found, the cell destroys itself.Over time and after many cell divisions, a third mutation mayarise. If the mutation gives the cell some further advantage, thatcell will grow more vigorously than its predecessors and thusspeed up the growth of the tumour.
  • 105. Fourth mutation• The new type of cells grow rapidly, allowing for moreopportunities for mutations. The next mutation pavesthe way for the development of an even more aggressivecancer.At this point the tumour is still contained as has notbroken basement membrane –carcinoma in situ.
  • 106. Breaking through the membrane• The newer, wilder cells created by another mutation are ableto push their way through the epithelial tissues basementmembrane, which is a meshwork of protein that normallycreates a barrier. The invasive cells in this tumour are nolonger contained.At this point the cancer is still too small to be detected.
  • 107. Angiogenesis• Often during the development of earlier stages of the tumour, orperhaps by the time the tumour has broken through thebasement membrane (as pictured above), angiogenesis takesplace. Angiogenesis is the recruitment of blood vessels from thenetwork of neighbouring vessels.• Without blood and the nutrients it carries, a tumour would beunable to continue growing. With the new bloodsupply, however, the growth of the tumour accelerates; it sooncontains thousand million cells and, now the size of a smallgrape, is large enough to be detected as a lump
  • 108. Invasion and dispersal• The tumour has now invaded the tissue beyond the basementmembrane.Individual cells from the tumour enter into the network ofnewly formed blood vessels, using these vessels as highwaysby which they can move to other parts of the body. A tumouras small as a gram can send out a million tumour cells intoblood vessels a day.
  • 109. Tumour cellstravel - metastasis• What makes mosttumours so lethal istheir ability tometastasize -- thatis, establish newtumour sites at otherlocations throughoutthe body.Secondary tumours.• Metastasis is nowunderway, as tumourcells from the originalcancer growth travelthroughout the body.Most of these cells willdie soon after enteringthe blood or lymphcirculation.
  • 110. Metastasis• To form a secondary tumour, a tumour cell needs to leave thevessel system and invade tissue. The cell must attach itself toa vessels wall. Once this is done, it can work its way throughthe vessel and enter the tissue.Although perhaps less than one in 10,000 tumour cells willsurvive long enough to establish a new tumour site, a fewsurvivors can escape and initiate new colonies of the cancer.
  • 111. Changes observed when a normal tissueculture cell is transforming to a tumor• Changes observed when a normal tissue cellis transforming to a tumour are as follows.• 1. Alterations in the nucleus• 2. Plasma membrane related abnormalities• 3. Adherence abnormalities• 4. Growth and division abnormalities• 5. Defective differentiation
  • 112. • 6. Inability to undergo apoptosis followingDNA damage• 7. Anaplasia: Loss of differentiation, meaningliterally “without form”• 8. Cell division fixes the mutation in daughtercells• 9. hyperplasia and stimulate growth• 10.loose control over the cell division process• 11.do not adhere to each other• 12.do not resemble normal cells• 13.do not carry out functions of normal cells
  • 113. • Dysplasia• Abnormal change in the size, shape, andorganization of cells in a tissue• Often an early step toward cancer• Microscopic characteristics of cancer cells• Behave differently from normal cells• they are precancerous stages and turn intocancer
  • 114. Growth Factors Regulate When Cells Divide
  • 115. NORMAL CELLGrowth factorGrowth factor receptorSignal transductionActivation oftranscriptioncytoplasmnucleus
  • 116. Relationship between gene products ofproto oncogeneGrowth factors eg IGFGrowth factor receptorsEg erb-2, retSignal transducingfactorsEg cytoplasmickinasesDNA binding proteinsconcerned withtranscriptioncell cycleproteins egcyclin D
  • 117. NEOPLASTIC CELLSIncreasedIn growthfactorIncreasedIn growthfactorreceptorsIncreased insignaltransductionIncrease inactivation oftranscription
  • 118. Length of TelomeresTelomeres are structuresat the ends ofchromosomes thatshorten with each celldivision. After 50divisions, the shortenedlength of telomerescauses mitosis to stop.telomeres
  • 119. Summary• Cancer develops through four definablestages:• initiation• promotion• progression• and malignant conversion.
  • 120. Summary• The first stage, initiation in which DNAdamage takes place• If repair does not take place will lead topromotion phase in which mutated cell isstimulated to grow and divide faster andbecomes a population of cells.
  • 121. Summary• During progression, there is further growthand expansion of the tumor cells over normalcells and leads then further mutations indaughter cells until conversion occurs and celldoes not resemble normal cell at all butbecomes a tumor cell
  • 122. Summary• In a 2000 article by Hanahan andWeinberg, the biological properties ofmalignant tumor cells were summarized asfollows
  • 123. Summary• Acquisition of self-sufficiency in growthsignals, leading to unchecked growth.• Loss of sensitivity to anti-growth signals, alsoleading to unchecked growth.• Loss of capacity for apoptosis, in order toallow growth despite genetic errors andexternal anti-growth signals.
  • 124. Summary• Loss of capacity for senescence, leading tolimitless replicative potential (immortality)• Acquisition of sustainedangiogenesis, allowing the tumor to growbeyond the limitations of passive nutrientdiffusion.
  • 125. Summary• Acquisition of ability to invade neighbouringtissues, the defining property of invasivecarcinoma.• Acquisition of ability to build metastases atdistant sites
  • 126. Classification of bronchogeniccarcinoma
  • 127. Classification of bronchogeniccarcinoma• Correct classification of lung cancer cases arenecessary to assure that lung cancer patientsreceive optimum management
  • 128. Classification of bronchogeniccarcinoma• There are two types of lung cancers• 1.Non-small cell lung cancer• 2.Small cell lung cancer
  • 129. Non-small cell lung cancer• Consist of three subtypes• Squamous cell (epidermoid) carcinoma• Adenocarcinoma (previously calledbronchioloalveolar carcinoma)• Large cell (undifferentiated) carcinoma
  • 130. Non-small cell lung cancer• The cells in these subtypes differ insize, shape, and chemical make-up whenlooked at under a microscope. But they aregrouped together because the approach totreatment and prognosis (outlook) are verysimilar.
  • 131. Squamous cell (epidermoid)carcinoma• These cancers start from squamouscells, which are flat cells that line inside of theairways in the lungs.
  • 132. Squamous cell (epidermoid)carcinoma• Squamous cellcarcinoma usually startsin one of the largerairways.Therefore, these tumorstend to be located inthe central area(middle)of the lung near thebronchus.
  • 133. Squamous cell (epidermoid)carcinoma• This form of NSCLC has decreased infrequency over the past three decades, but isstill the most common form of lung canceramong men who are current or formersmokers or over age 65 years of both sexes.
  • 134. Adenocarcinoma of lung• Adenocarcinoma is a cancer of an epitheliumthat originates in glandular tissue.Adenocarcinoma of the lung tends to stainmucin positive as it is derived from the mucusproducing glands of the lungs.
  • 135. Adenocarcinoma of lung• Similar to other adenocarcinoma, if this tumoris well differentiated (low grade) it willresemble the normal glandular structure.
  • 136. Adenocarcinoma of lung• Poorly differentiated adenocarcinoma will notresemble the normal glands (high grade) andwill be detected by seeing that they stainpositive for mucin (which the glands produce).
  • 137. Adenocarcinoma of lung• This cancer usually is seenperipherally in the lungs, asopposed to small cell lungcancer and squamous cell lungcancer, which both tend to bemore centrally located,
  • 138. Adenocarcinoma of lung• Generally, adenocarcinomas grow more slowlythan the other subtypes.
  • 139. Adenocarcinoma of lung• Adenocarcinoma is a non-smallcell lung carcinoma, and assuch, it is not as responsive toradiation therapy as is small celllung carcinoma, but is rathertreated surgically, for exampleby pneumonectomy orlobectomy.
  • 140. Adenocarcinoma of lung• The solitary appearance of this neoplasmsuggests that the tumor is primary rather thanmetastatic.
  • 141. Adenocarcinoma of lung• Adenocarcinoma is themost common form oflung cancer found inwomen, and is oftenfound in non-smokers.
  • 142. Adenocarcinoma of lung• Most common type of lung cancer among allAsians.• Appears to be increasing in young, non-smoking women.
  • 143. Adenocarcinoma of lung• Lung adenocarcinoma has been increasing inrecent years, whereas another form of non-small cell lung cancer, squamous cellcarcinoma, has been decreasing. It is thoughtby some that the addition of filters tocigarettes allows smoke to be inhaled moredeeply into the lungs where adenocarcinomaoccurs.
  • 144. Adenocarcinoma of lung• Because lung adenocarcinoma often begins inthe outer parts of the lungs, well-knownsymptoms of lung cancer such as a chroniccough and coughing up blood may be lesscommon until later in the disease.
  • 145. Adenocarcinoma of lung• Seen here is the multifocalvariant
  • 146. Adenocarcinoma of lung• that appears grossly as apneumonic consolidation.• Most of the upper lobe towardthe right has a pale tan to greyappearance.
  • 147. Adenocarcinoma of lung• Microscopically, the bronchioloalveolarcarcinoma is composed of columnar cells thatproliferate along the framework of alveolarseptae. The cells are well-differentiated. Theseneoplasms in general have a better prognosisthan most other primary lung cancers.
  • 148. Large cell (undifferentiated)carcinoma• It may appear in anypart of the lung. It tendsto grow and spreadquickly, which can makeit harder to treat.
  • 149. Large cell (undifferentiated)carcinoma• The cells of large cellcarcinoma (LCC) are thelargest of the varioustypes of NSCLC. Thecells are generallyhighly undifferentiatedor immature inappearance.
  • 150. Large cell (undifferentiated)carcinoma• Some experts believe these tumors representadenocarcinomas or squamous cellcarcinomas that are so undifferentiated as tobe unrecognizable.
  • 151. Large cell (undifferentiated)carcinoma• The prognosis for large cell carcinoma isgenerally less favorable than for other formsof NSCLC.
  • 152. OTHER CANCERS IN THE LUNGS• There are other types of non-epithelialcancers that arise in the lungs. They are allrelatively uncommon compared to SCLC andNSCLC.
  • 153. OTHER CANCERS IN THE LUNGS• Examples of these cancers include• Carcinoid tumors, malignant pleuralmesotheliomas, fibrosarcomas, andleiomyosarcomas. The lungs are also afrequent location for metastatic tumors fromother locations in the body.
  • 154. SMALL (OAT) CELL CARCINOMA• Small (Oat) cellcarcinoma accounts forabout 20-30% of all lungcancers• It has, in the past, beencalled oat cell cancerbecause the cellsresemble oat grains.
  • 155. SMALL (OAT) CELL CARCINOMA• when seen under amicroscope the cellsappear small round oroval, or shaped like oatgrains.
  • 156. SMALL (OAT) CELL CARCINOMA• it is thought to originate from neuroendocrinecells (APUD cells) in the bronchus calledFeyrter cells (named for Friedrich Feyrter)• Hence, they express a variety ofneuroendocrine markers, and may lead toectopic production of hormones like ADH andACTH that may result in paraneoplasticsyndromes and Cushings syndrome.
  • 157. SMALL (OAT) CELL CARCINOMA• The tumor cells cause increased secretion ofadrenocorticotropic hormone (a hormonefrom the adrenal gland), causing Cushing’sdisease, which is characterized by a puffy face,weight gain, hump on the lower neck, orelevated blood sugar levels.
  • 158. SMALL (OAT) CELL CARCINOMA• Antidiuretic hormone, also secreted by thesetumor cells, lead to water retention and lowsodium, which(SIADH)can cause confusion.Small cell carcinoma antibodies also can causeweakness by the tumor-producing antibodiesagainst normal tissues (autoantibodies).
  • 159. SMALL (OAT) CELL CARCINOMA• Small cell lung cancer is a neuroendocrinecarcinoma that exhibits aggressive behavior, rapidgrowth, early spread to distant sites, exquisitesensitivity to chemotherapy and radiation, andfrequent association with distinct paraneoplasticsyndromes.• The cancer spreads easily because of the constantflow of blood and lymph through the lungs. Thefluids can carry cancer cells to the otherlung, lymph nodes, and organs outside of thechest.
  • 160. SMALL (OAT) CELL CARCINOMA• There is usually early involvement of the hilarand mediastinal lymph nodes.
  • 161. SMALL (OAT) CELL CARCINOMA• Prognosis• In limited-stage disease, median survival withtreatment is 14–20 months, and about 20% ofpatients with limited-stage small-cell lungcarcinoma live 5 years or longer.
  • 162. SMALL (OAT) CELL CARCINOMA• The prognosis is far worse in extensive-stagesmall-cell lung carcinoma, withtreatment, median survival is just 8–13months, and only 1–5% of patients withextensive-stage small-cell lung carcinomatreated with chemotherapy live 5 years orlonger.
  • 163. SMALL (OAT) CELL CARCINOMA• Approximately half of all individuals diagnosedwith Lambert-Eaton myasthenic syndrome(LEMS) will eventually be found to have asmall-cell carcinoma of the lung.
  • 164. SMALL (OAT) CELL CARCINOMA• Arising centrally in thislung and spreadingextensively is a smallcell anaplastic (oat cell)carcinoma. The cutsurface of this tumorhas asoft, lobulated, white totan appearance.
  • 165. SMALL (OAT) CELL CARCINOMA• The tumor seen here hascaused obstruction of themain bronchus to leftlung so that the distallung is collapsed. Oat cellcarcinomas are veryaggressive and oftenmetastasize widely beforethe primary tumor massin the lung reaches a largesize.
  • 166. SMALL (OAT) CELL CARCINOMA• Here is an oat cellcarcinoma which isspreading along thebronchi. The speckledblack rounded areasrepresent hilar lymphnodes with metastaticcarcinoma.
  • 167. SMALL (OAT) CELL CARCINOMA• These neoplasms aremore amenable tochemotherapy thanradiation therapy orsurgery, but theprognosis is still poor.Oat cell carcinomasoccur almost exclusivelyin smokers.
  • 168. SMALL (OAT) CELL CARCINOMA• This is the microscopicpattern of a small cellanaplastic (oat cell)carcinoma in whichsmall dark blue cellswith minimal cytoplasmare packed together insheets.
  • 169. Pulmonary Hamartoma• Here are two examplesof a benign lungneoplasm known as apulmonary hamartoma.
  • 170. Pulmonary Hamartoma• These uncommonlesions appear on chestradiograph as a "coinlesion" that has adifferential diagnosis ofgranuloma and localizedmalignant neoplasm.
  • 171. Pulmonary Hamartoma• They are firm anddiscreet and often havecalcifications in themthat also appear onradiography. Most aresmall (less than 2 cm).
  • 172. Metastatic carcinoma• Multiple variably-sizedmasses are seen in alllung fields. These tan-white nodules arecharacteristic formetastatic carcinoma.
  • 173. Metastatic carcinoma• Metastases to the lungs aremore common even thanprimary lung neoplasmssimply because so manyother primary tumors canmetastasize to the lungs.Even the hilar nodes in thisphotograph demonstratenodules of metastaticcarcinoma. The nodules areusually in the periphery anddo not cause majorobstruction.
  • 174. Mesothelioma• The dense whiteencircling tumor mass isarising from the visceralpleura and is amesothelioma. Theseare big bulky tumorsthat can fill the chestcavity.
  • 175. Mesothelioma• The risk factor formesothelioma isasbestos exposure.
  • 176. Signs symptoms of bronchogeniccarcinoma
  • 177. Signs symptoms of bronchogeniccarcinoma• Persistent cough• Persistent haemoptysis• Persistent wheeze & stridor• Persistent dyspnea
  • 178. Signs symptoms of bronchogeniccarcinoma• Pneumonitis fever productive cough• Chest pain from pleural or chest wallinvolvement• Symptoms of lung abcess from tumourcavitation
  • 179. Signs symptoms of bronchogeniccarcinoma• Haematogenous,lymphatic or direct spread topleura resulting in malignant pleural effusion• Superior vena caval obstruction resulting insuperior vena caval syndrome• Tracheal obstruction leading to stridor anddyspnea
  • 180. Signs symptoms of bronchogeniccarcinoma• Oesophageal obstruction leading to dysphagia• Recurrent laryngeal nerve involvement withresultant hoarsness of voice and bovine cough• Phrenic nerve involvement resulting indiaphragmatic paralysis and dyspnea
  • 181. Signs symptoms of bronchogeniccarcinoma• Sympathetic chain involvement leading tohorners syndrome(pancosts tumour)• Direct extension to chest wall resulting in ribpain and pathological fractures, intercostalneuralgia• T1 involvement• Pericardial and cardiac involvement withresultant cardiac temponade,arrythemias orcardiac failure
  • 182. Metastasis to other organs• Brain metastasis with neurological deficits• Bone metastasis• Bone marrow involvement with pancytopenia• Liver metastasis• Lymph node metastasis• Metastasis to spinal cord & cord compression
  • 183. Paraneoplastic syndrome(Result frompeptide secretion of tumour)• Endocrine• SIADH-Syndrome of inappropriate secretion ofantidiuretic hormone• resulting in hyponatremia,cushingssyndrome, ectopic production of parathyroidhormone resulting in hypercalcaemia andhypophosphatemia
  • 184. Paraneoplastic syndrome(Result frompeptide secretion of tumour)• Neuromuscular• Eaton Lambert syndrome, peripheralneuropathy,cerebellar degeneration, corticaldegeneration,polymyositis
  • 185. Paraneoplastic syndrome(Result frompeptide secretion of tumour)• Skeletal• Clubbing ,hypertrophic pulmonaryosteoarthropathy
  • 186. Paraneoplastic syndrome(Result frompeptide secretion of tumour)• Haematological• Migratory venousthrombophelbitis(Trousseaussyndrome),DIC,anaemia,granulocytosis orpancytopenia
  • 187. Paraneoplastic syndrome(Result frompeptide secretion of tumour)• Cutaneous• Dermatomyositis,acanthosis nigricans• Renal• Nephrotic syndrome,glomerulonaphritis• and many more
  • 188. Investigations• x ray chest• May show opacity,cavitation,effusion,collapse orconsolidation• Unilateral enlargement at hilum ,glandularenlargement• Mediastinal widening due to mediastinalinvolvement• etc etc
  • 189. Investigations• Cytological examination of the following may bepositive for malignant cells• Sputum• Bronchial brushing• Bronchial washings• Percutaneous needle aspiration biopsy ofperipheral tumour• Fine needle aspiration of lymph node, skin orliver
  • 190. Investigations• CT SCAN(computed tomography) of chest andabdomen• is an important investigation for staging• Evaluation of tumour size• CT guided biopsy• To assess response to treatment
  • 191. Investigations• Bronchoscopy• For visualisation and biopsy of intrabronchialtumour• Collection of bronchial washings
  • 192. Other investigations• Scalene node biopsy• Mediastonoscopy• Pleural aspiration and biopsy• Barium swallow• Ultrasound abdomen• Bone scans• Bone marrow biopsy• CT brain• Whole body scan spine etc• Then all other routine tests and full blood count

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