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1.  Increased Proteolysis, Myosin Depletion, and Atrophic AKT-FOXO Signaling in Human Diaphragm Disuse 
Rationale: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy.
Objectives: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse.
Methods: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours.
Measurements and Main Results: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and α-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates.
Conclusions: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse.
PMCID: PMC3056225  PMID: 20833824
AKT; FOXO; ubiquitination; proteasome; myosin heavy chains
2.  Mediastinal mature teratoma in a Jehovah's Witness: Discrepancy between imaging and intraoperative findings 
Primary mediastinal germ cell tumors are exceedingly rare but may present with a wide spectrum of elements. The occasional mediastinal teratoma that presents completely comprised of mature elements is a benign tumor but the appearance on imaging studies may be more suggestive of an invasive tumor. The treatment is complete resection but the assessment of resectability based on computed tomographic imaging can be misleading.
Presentation of case
We present a case of a 26 year old female, Jehovah's Witness who presented with a symptomatic mediastinal mass that on CT scan appeared to be unresectable due to presumed invasion of adjacent structures including the left pulmonary artery. Surgical exploration revealed an encapsulated, completely resectable mass which was excised without difficulty. Her early postoperative course was uneventful and at 18 months follow up is doing well without evidence of recurrence.
The treatment of mature teratoma is complete surgical excision but the imaging studies may at times be misleading. We believe this case presents a unique clinical situation, since mediastinal mature teratomas are very rare and in addition, the preoperative decision to excise a mass becomes more complex in a case of a Jehovah's Witness. This case illustrates that the CT findings may be misleading when assessing a mediastinal mass.
Resectability of a mediastinal mass can only be assessed at the time of operation and rarely should operation be denied solely on the basis of findings on imaging. Thus in these primary mediastinal tumors there should be a low threshold for proceeding with operation.
PMCID: PMC3267256  PMID: 22288043
Mediastinal mass; Mature teratoma
3.  Systemic Blockade of Transforming Growth Factor-β (TGF-β) Signaling Augments the Efficacy of Immunogene Therapy 
Cancer research  2008;68(24):10247-10256.
Locally-produced TGF-β promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This paper explores the potential for increased efficacy when combining immunotherapies with TGF-β suppression using the TGF-β type I receptor kinase inhibitor, SM16. Adenovirus expressing IFNβ (Ad.IFNβ) was injected intratumorally once in established subcutaneous AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a K-ras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing HPV-E7 (Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine-expression and cell populations were measured in tumors and spleens by real time-PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.INFβ increased the number of intratumoral leukocytes (including macrophages, NK cells, and CD8+ cells) and increased the percentage of T-cells expressing the activation marker CD25. SM16 also augmented the anti-tumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8+ T cells in the spleens, but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-β signaling pathway augments the anti-tumor effects of Ad.INFβ immune-activating or Ad.E7 vaccination therapy. The addition of TGF-β blocking agents in clinical trials of immunotherapies may increase efficacy.
PMCID: PMC2637471  PMID: 19074893
tumor immunology; immunosuppression; TGFβ; tumor associated macrophages; cytokines; lung cancer; mesothelioma; tumor vaccine; interferon-β
4.  TGF-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers 
Adoptive cellular immunotherapy has promise as an approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T-cells at the effector phase.
Transforming growth factor-β (TGF-β) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-β signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy.
Experimental Design
Flank tumors were generated in mice using the OVA-albumin (OA) expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T-cells recognize an immunodominant peptide in OA) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-β receptor-I kinase blocker (SM16).
We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-β receptor blockade increased the persistence of adoptively transferred T-cells in the spleen and lymph nodes, increased numbers of adoptively transferred T-cells within tumors, increased activation of these infiltrating T-cells, and altered the tumor microenvironment with a significant increase in TNF-α and decrease in arginase mRNA expression
We found that systemic blockade of TGF-β receptor activity augmented the anti-tumor activity of adoptively transferred T-cells and may thus be a useful adjunct in future clinical trials.
PMCID: PMC2491721  PMID: 18559619
tumor immunology; immunosuppression; TGFβ; Cytotoxic T-cells; cytokines; adoptive transfer
5.  Sleep and quality of life in long-term lung cancer survivors 
Sleep problems are common in lung cancer survivors, yet little is known about the prevalence, determinants, and the effects on quality of life (QoL) of these sleep problems in long-term lung cancer survivors.
A case-control study design comparing 76 elderly lung cancer survivors (LCS, >5 years post diagnosis with mean survival time of 8 years +/- 2.1 years) and 78 elderly non-cancer controls (NCC). Measurements included a standardized questionnaire for sleep (Pittsburgh Sleep Quality Index--PSQI), and analogue scales for dyspnea, pain, and other comorbid symptoms, as well as demographic factors and cancer history.
Overall, 56.6% of LCS had poor sleep (PSQI global score>5) as compared to only 29.5% of NCC (p<0.001), and 49.2% of LCS who did not have sleep difficulties prior to their lung cancer diagnosis ultimately developed them. There was also evidence of significant impairments in sleep efficiency in LCS (78.3%) relative to NCC (89.6%, p<0.001), predominantly due to increased nocturnal awakenings. A single-item analogue scale for sleep quality was not as effective in identifying sleep problems as more specific questions about sleep duration and sleep efficiency. Poor sleep quality was significantly correlated with impairments in quality of life, even when controlling for other factors, such as dyspnea.
Even 8 years after diagnosis, LCS continue to have significant sleep difficulties. By asking specific questions about sleep medication use, nocturnal awakenings and sleep efficiency, health care providers can identify sleep problems that could be treated and potentially improve the quality of life of their patients.
PMCID: PMC2206246  PMID: 17765353
Lung cancer; sleep disorders; cancer survivor; aged; quality of life; long-term survival

Results 1-5 (5)