Academic Background:

BS (Cell Biology), 1979, Cornell University, Ithaca, NY

MD, 1984, Brown University, Providence, Rhode Island

Resident, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania,   Philadelphia, PA   1984-1988  

Cytopathology Fellow with Prabodh Gupta, Hospital of the University of Pennsylvania, Philadelphia, PA   1988-1989  

Academic Interests:

Cytology is the field that uses the smallest possible biopsy for diagnosis, by identifying structural changes in cells and small tissue fragments.   My basic research interest has been to try to define diagnostic structural changes in molecular terms (see Basic Science Research Interest below). 

My clinical interest is fine needle aspiration (FNA) biopsy.  FNAs are minimally invasive, safe, rapid, and relatively painless means of definitive diagnosis.  Having performed over 2,500 FNAs in my career so far, a UMASS FNA Clinic has been started whereby a Cytopathologist performs and immediately interprets the FNA.  It is more efficient for cytopathologists to perform the biopsy that they diagnose. 

I have also been interested in developing technical solutions to the problem of acquiring and processing microsized pieces of tissue for diagnosis.  Through grants from the Department of Pathology and the University of Massachusetts, I invented the Cellient^TM Automated Cell Block System (US Patents 6,913,921 and 7,541,161, with three other pending patents).  Licensed to Hologic Corporation in Marlborough, MA, Cellient^TM automatically recovers small tissue fragments from a specimen container and rapidly delivers them to an indexable plane in paraffin for histologic sectioning, in under one hour.  Cellient^TM allows fine needle (22-25 guage) biopsies to be examined in essentially the same manner as much larger core biopsies.  Several other invention disclosures to the Office of Technology Management at UMASS have been made relating to improving microbiopsy needles, assessing the quality of a microbiopsy sample at the bedside, and developing automated means of processing and embedding histology samples.   

As criteria become defined at a molecular level, and techniques for procuring and handling micro-sized biopsies are developed, most cancers can be diagnosed with minimally invasive, rapid, and safe cytologic techniques. 

Basic Science Research Interests:

In spite of years of progress in cancer research, the diagnosis of cancer still generally requires a pathologist to examine a biopsy by light microscopy.  Cytopathologists are experts at recognizing changes in cell structure that are diagnostic of various cancers.   Surprisingly, cancer researchers still know very little about how or why cancer cells are structured differently from normal cells.  My long term goal is to learn the biochemical basis and functional significance of diagnostic changes in the nuclear structure of cancer cells.  My lab has developed the idea that cellular-level structural changes diagnostic of cancer are directly caused by the particular cancer genes active in that cancer.   We have linked 8 different cancer genes to large scale cellular structural changes, involving chromatin and the nuclear envelope, characteristic of different types of cancers.  We think that the structural changes oncogenes induce during their activation provide an essential insight into the functional changes that occur during carcinogenesis. 

Nuclear envelope irregularity and changes in large-scale chromatin organization are important diagnostic alterations in many forms of cancer.  We are focused on a pair of tyrosine kinases—RET/PTC and TRK/PTC—that induce the nuclear envelope irregularity and chromatin dispersal diagnostic of papillary thyroid carcinoma.  We have determined the phosphotyrosine docking site on these kinases that mediates these changes.  We showed that the nuclear lamina composition is very similar between papillary thyroid carcinomas and normal thyroid, and histone composition at a global level is not apparently altered for H3K4m, H3K9m, H3K9/14Ac, and H3K27m.  Using micro-injection of RET/PTC into normal thyroid cells in culture, we showed that nuclear envelope irregularity develops during interphase, without an intervening post-mitotic nuclear envelope reassembly, because the nuclear envelope is distorted actively during interphase by forces exerted on it from the cytoskeleton and/or chromatin.  More recently, we confirmed that there are active interphase deflections of the nuclear lamina in prostate cancer, and we found that depolymerization of actin or microtubules does not inhibit these dynamics.  My lab is interested in developing live cell imaging techniques that can be applied to organ cultures to study the dynamics of nuclear lamina alterations in cancer cells and dependence of lamina dynamics on cell cycle phase or active transcription.      

The paradigm that cancer genes are linked very directly to diagnostic cell structural changes should lead to improved diagnosis of cancer, insight into novel cell physiologies involving chromatin and the nuclear envelope, and a basis for a large-scale screen for novel anticancer drugs. Live cell imaging techniques seem likely to expose new sets of dynamic structural changes with a diagnostic utility surpassing that of classical static imaging.