Supplementary Materials and Methods: Immunohistochemistry, Immunofluorescence, TUNEL staining Sup... more Supplementary Materials and Methods: Immunohistochemistry, Immunofluorescence, TUNEL staining Supplementary Figure S1. Treatment with MI-773 and/or cisplatin is not toxic to mice. Graph depicting mouse weight during the experimental period. Data were normalized against pre-treatment weight. Supplementary Figure S2. Representative photomicrographs of UM-HACC-5 and -6 cells exposed to 1 μM MI-773 and/or 2 μM cisplatin, or vehicle control, for 72 hours in vitro. Supplementary Figure S3. Representative graphs depicting the number of UM-HACC-5 (A) and -6 (B) cells in each cell-cycle phase after treatment with 1 μM MI-773 and/or 2 μM cisplatin, or vehicle control, for 24 hours. Supplementary Figure S4. Representative photomicrographs obtained by immunofluorescence for ALDH (green) in UM-PDX-HACC-5 tumors treated with MI-773 and/or cisplatin. ALDH-positive cells are predominantly observed in vehicle and cisplatin groups (details) and are apparently located in close proximity to blood vesse...
Journal of Oral and Maxillofacial Surgery, Oct 1, 2021
Background. Distraction osteogenesis is an established technique for the lengthening of long bone... more Background. Distraction osteogenesis is an established technique for the lengthening of long bones and correction of selected craniofacial deformities. Regenerate osteoid bone matrix formed during the distraction phase is malleable and can recreate the three-dimensional form of native bones. Animal experiments and early clinical experience have confirmed that distraction osteogenesis can be used for the reconstruction of segmental bony defects. Herein we discuss the principles of distraction osteogenesis in reference to reconstruction of segmental bony defects and report its clinical application of the mandible continuity defects. Patients and Methods. Four patients (age, 7-83 years) with critical segmental mandibular defects (range, 3.5 cm-6.5 cm), resulting from ablative oncologic head and neck surgery underwent primary mandibular reconstruction by transport distraction osteogenesis. Two defects were at the angle and body region, one at the body, and the other at the parasymphysis and body region. Synthes Titanium Multi-vector and Leibinger Multi-guide distractors in bifocal (n = 2) and trifocal (n = 2) architecture were used after the stabilization of the segmental continuity defect using a defect-bridging mandibular reconstruction plate. Osteo-distraction was carried out at a rate of 1 mm per day, with once or twice a day rhythm, after a 1-week latency period. The consolidation period was equal to the period of distraction. Results. All patients tolerated the distraction procedure. Satisfactory bone formation was observed in two patients, and partial bone formation was seen in one patient. Treatment failure was encountered in one patient who had a second oral cavity primary tumor observed during the consolidation period, requiring interruption of the treatment sequence. Conclusions. Mandibular reconstruction with distraction osteogenesis is a potentially useful technique in selected patients with segmental mandibular continuity defects after ablative head and neck cancer surgery.
International Journal of Oral and Maxillofacial Surgery, May 1, 2019
Conclusion: We advocate throughout preoperative planning with the use of the low-cost printers an... more Conclusion: We advocate throughout preoperative planning with the use of the low-cost printers and templates, which enhance benefit for the patients, as well as a great help for the surgeons, resulting in shorter operation time and better outcome.
Purpose: Unique cells characterized by multipotency, selfrenewal, and high tumorigenic potential ... more Purpose: Unique cells characterized by multipotency, selfrenewal, and high tumorigenic potential have been recently discovered in mucoepidermoid carcinomas. These cells are defined by high aldehyde dehydrogenase activity and high CD44 expression (ALDH high CD44 high) and function as cancer stem cells (CSC). It has been recently shown that p53 regulates cell differentiation, suggesting that induction of p53 by therapeutic blockade of the MDM2-p53 interaction may constitute a novel strategy to ablate CSCs. Here, we evaluated the effect of a small-molecule inhibitor of MDM2-p53 interaction (MI-773) on the fraction of CSCs in mucoepidermoid carcinoma. Experimental Design: Human mucoepidermoid carcinoma cells (UM-HMC-1,-3A,-3B) were used to assess the effect of MI-773 on cell survival, cell cycle, fraction of CSCs, and expression of p53, p21, MDM2, and Bmi-1 (key regulator of self-renewal). Mice bearing xenograft tumors generated with these mucoepidermoid carcinoma cells were treated with MI-773 to determine the effect of MDM2-p53 inhibition on CSCs in vivo. Results: MDM2 is highly expressed in human mucoepidermoid carcinoma tissues. MI-773 induced expression of p53 and its downstream targets p21 and MDM2, caused G 1 cell-cycle arrest, and induced mucoepidermoid carcinoma tumor cell apoptosis in vitro. Importantly, a marked decrease in expression of Bmi-1 and in the fraction of ALDH high CD44 high (CSCs) was caused by MI-773 in vitro and in mice harboring mucoepidermoid carcinoma xenografts. Conclusions: Collectively, these data demonstrate that MI-773 reduces the fraction of CSCs, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction.
Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC... more Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A,-2B,-5,-6) in vitro. The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression. Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-x L , and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P ¼ 0.0097). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction. Clin Cancer Res; 23(4); 1036-48. Ó2016 AACR.
This reflection describes a life-limiting case of oral squamous cell carcinoma (SCC) that require... more This reflection describes a life-limiting case of oral squamous cell carcinoma (SCC) that required thoughtful management facilitated by an advance care plan (ACP). A 70-year-old female was diagnosed with a T4aN2bM0 biopsy-proven invasive, welldifferentiated keratinizing SCC. Surgical wide-local excision included teeth #11-16 with left unilateral neck dissection, levels I-V. She was rehabilitated with maxillary obturator prosthesis and underwent chemoradiation therapy. Her course was complicated by dysphagia and trismus. She experienced multiple recurrences. At a certain point, negative margins could not be achieved without facial disfigurement. The patient, her husband, and providers decided together that further management would be palliative. Before the additional surgical procedures, she communicated a thorough ACP with her husband and providers who were prepared to facilitate difficult care decisions on her behalf. The patient passed away at home with hospice care at the age of 74. This motivated patient with oral SCC and impactful postmanagement complications appreciated the clarity of an ACP. Her values and goals of care were incorporated with ongoing communication and documentation of this plan, which was instrumental in facilitating her person-centered care. The providers apply lessons learned here in future practice and education of residents and students.
Epilepsy is a relatively common neurological disorder with incidence in both developed and develo... more Epilepsy is a relatively common neurological disorder with incidence in both developed and developing countries. Head, facial, and oral injuries can result from seizures experienced by the epileptic patient. Patients with severe epilepsy often experience other dental disease due to their inability to properly maintain their oral hygiene. This paper presents a case of a chronic mandibular fracture following an episode of seizures in a patient with epilepsy in whom the fracture was discovered when he developed a fistula in the submandibular region.
ATP-dependent Caz+ transport was studied in basolateral membrane vesicles prepared from rat parot... more ATP-dependent Caz+ transport was studied in basolateral membrane vesicles prepared from rat parotid gland slices incubated without or with agents which increase cyclic AMP. Isoproterenol (lo-' M), forskolin (2 x lo-' M) and 8-bromocyclic AMP (2 x M) all increased ATP-dependent "Ca2+ uptake 1.5-to 3-fold. The effect of isoproterenol was concentration-dependent and blocked by the @-adrenergic antagonist propranolol. Enhanced uptake did not appear an artifact of vesicle preparation as apparent vesicle sidedness, 4'Ca2+ efflux rates, specific activity of marker enzymes and equilibrium Ca2+ content were identical in vesicle preparations from control and 8-bromocyclic AMPtreated slices. Kinetic studies showed the ATP-dependent Ca2+ transport system in vesicles from B-bromocyclic AMP-treated slices displayed a-50% increase in Vmax and in K,,, Ca2+, compared to controls. The data suggest that physiological secretory stimuli to rat parotid acinar cells, which involve cyclic AMP, result in a readjustment of the basolateral membrane ATP-dependent Ca2+ pump. In nonexcitable mammalian tissues, plasma membrane ATP-dependent Ca2+ transport, presumably via a (Ca2+, Mg2+)-ATPase, constitutes the principal means of extruding Ca2+ against its steep electrochemical gradient (e.g. 1, 2). The
International Journal of Oral Surgery, Dec 1, 1984
Conservative and surgical methods are used to treat chronic dislocations of the temporomandibular... more Conservative and surgical methods are used to treat chronic dislocations of the temporomandibular joint. Different techniques described in the literature are discussed. 8 cases treated by eminectomy are presented and the results are evaluated.
Supplementary Materials and Methods: Immunohistochemistry, Immunofluorescence, TUNEL staining Sup... more Supplementary Materials and Methods: Immunohistochemistry, Immunofluorescence, TUNEL staining Supplementary Figure S1. Treatment with MI-773 and/or cisplatin is not toxic to mice. Graph depicting mouse weight during the experimental period. Data were normalized against pre-treatment weight. Supplementary Figure S2. Representative photomicrographs of UM-HACC-5 and -6 cells exposed to 1 μM MI-773 and/or 2 μM cisplatin, or vehicle control, for 72 hours in vitro. Supplementary Figure S3. Representative graphs depicting the number of UM-HACC-5 (A) and -6 (B) cells in each cell-cycle phase after treatment with 1 μM MI-773 and/or 2 μM cisplatin, or vehicle control, for 24 hours. Supplementary Figure S4. Representative photomicrographs obtained by immunofluorescence for ALDH (green) in UM-PDX-HACC-5 tumors treated with MI-773 and/or cisplatin. ALDH-positive cells are predominantly observed in vehicle and cisplatin groups (details) and are apparently located in close proximity to blood vesse...
Journal of Oral and Maxillofacial Surgery, Oct 1, 2021
Background. Distraction osteogenesis is an established technique for the lengthening of long bone... more Background. Distraction osteogenesis is an established technique for the lengthening of long bones and correction of selected craniofacial deformities. Regenerate osteoid bone matrix formed during the distraction phase is malleable and can recreate the three-dimensional form of native bones. Animal experiments and early clinical experience have confirmed that distraction osteogenesis can be used for the reconstruction of segmental bony defects. Herein we discuss the principles of distraction osteogenesis in reference to reconstruction of segmental bony defects and report its clinical application of the mandible continuity defects. Patients and Methods. Four patients (age, 7-83 years) with critical segmental mandibular defects (range, 3.5 cm-6.5 cm), resulting from ablative oncologic head and neck surgery underwent primary mandibular reconstruction by transport distraction osteogenesis. Two defects were at the angle and body region, one at the body, and the other at the parasymphysis and body region. Synthes Titanium Multi-vector and Leibinger Multi-guide distractors in bifocal (n = 2) and trifocal (n = 2) architecture were used after the stabilization of the segmental continuity defect using a defect-bridging mandibular reconstruction plate. Osteo-distraction was carried out at a rate of 1 mm per day, with once or twice a day rhythm, after a 1-week latency period. The consolidation period was equal to the period of distraction. Results. All patients tolerated the distraction procedure. Satisfactory bone formation was observed in two patients, and partial bone formation was seen in one patient. Treatment failure was encountered in one patient who had a second oral cavity primary tumor observed during the consolidation period, requiring interruption of the treatment sequence. Conclusions. Mandibular reconstruction with distraction osteogenesis is a potentially useful technique in selected patients with segmental mandibular continuity defects after ablative head and neck cancer surgery.
International Journal of Oral and Maxillofacial Surgery, May 1, 2019
Conclusion: We advocate throughout preoperative planning with the use of the low-cost printers an... more Conclusion: We advocate throughout preoperative planning with the use of the low-cost printers and templates, which enhance benefit for the patients, as well as a great help for the surgeons, resulting in shorter operation time and better outcome.
Purpose: Unique cells characterized by multipotency, selfrenewal, and high tumorigenic potential ... more Purpose: Unique cells characterized by multipotency, selfrenewal, and high tumorigenic potential have been recently discovered in mucoepidermoid carcinomas. These cells are defined by high aldehyde dehydrogenase activity and high CD44 expression (ALDH high CD44 high) and function as cancer stem cells (CSC). It has been recently shown that p53 regulates cell differentiation, suggesting that induction of p53 by therapeutic blockade of the MDM2-p53 interaction may constitute a novel strategy to ablate CSCs. Here, we evaluated the effect of a small-molecule inhibitor of MDM2-p53 interaction (MI-773) on the fraction of CSCs in mucoepidermoid carcinoma. Experimental Design: Human mucoepidermoid carcinoma cells (UM-HMC-1,-3A,-3B) were used to assess the effect of MI-773 on cell survival, cell cycle, fraction of CSCs, and expression of p53, p21, MDM2, and Bmi-1 (key regulator of self-renewal). Mice bearing xenograft tumors generated with these mucoepidermoid carcinoma cells were treated with MI-773 to determine the effect of MDM2-p53 inhibition on CSCs in vivo. Results: MDM2 is highly expressed in human mucoepidermoid carcinoma tissues. MI-773 induced expression of p53 and its downstream targets p21 and MDM2, caused G 1 cell-cycle arrest, and induced mucoepidermoid carcinoma tumor cell apoptosis in vitro. Importantly, a marked decrease in expression of Bmi-1 and in the fraction of ALDH high CD44 high (CSCs) was caused by MI-773 in vitro and in mice harboring mucoepidermoid carcinoma xenografts. Conclusions: Collectively, these data demonstrate that MI-773 reduces the fraction of CSCs, suggesting that patients with mucoepidermoid carcinoma might benefit from therapeutic inhibition of the MDM2-p53 interaction.
Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC... more Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A,-2B,-5,-6) in vitro. The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression. Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-x L , and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P ¼ 0.0097). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction. Clin Cancer Res; 23(4); 1036-48. Ó2016 AACR.
This reflection describes a life-limiting case of oral squamous cell carcinoma (SCC) that require... more This reflection describes a life-limiting case of oral squamous cell carcinoma (SCC) that required thoughtful management facilitated by an advance care plan (ACP). A 70-year-old female was diagnosed with a T4aN2bM0 biopsy-proven invasive, welldifferentiated keratinizing SCC. Surgical wide-local excision included teeth #11-16 with left unilateral neck dissection, levels I-V. She was rehabilitated with maxillary obturator prosthesis and underwent chemoradiation therapy. Her course was complicated by dysphagia and trismus. She experienced multiple recurrences. At a certain point, negative margins could not be achieved without facial disfigurement. The patient, her husband, and providers decided together that further management would be palliative. Before the additional surgical procedures, she communicated a thorough ACP with her husband and providers who were prepared to facilitate difficult care decisions on her behalf. The patient passed away at home with hospice care at the age of 74. This motivated patient with oral SCC and impactful postmanagement complications appreciated the clarity of an ACP. Her values and goals of care were incorporated with ongoing communication and documentation of this plan, which was instrumental in facilitating her person-centered care. The providers apply lessons learned here in future practice and education of residents and students.
Epilepsy is a relatively common neurological disorder with incidence in both developed and develo... more Epilepsy is a relatively common neurological disorder with incidence in both developed and developing countries. Head, facial, and oral injuries can result from seizures experienced by the epileptic patient. Patients with severe epilepsy often experience other dental disease due to their inability to properly maintain their oral hygiene. This paper presents a case of a chronic mandibular fracture following an episode of seizures in a patient with epilepsy in whom the fracture was discovered when he developed a fistula in the submandibular region.
ATP-dependent Caz+ transport was studied in basolateral membrane vesicles prepared from rat parot... more ATP-dependent Caz+ transport was studied in basolateral membrane vesicles prepared from rat parotid gland slices incubated without or with agents which increase cyclic AMP. Isoproterenol (lo-' M), forskolin (2 x lo-' M) and 8-bromocyclic AMP (2 x M) all increased ATP-dependent "Ca2+ uptake 1.5-to 3-fold. The effect of isoproterenol was concentration-dependent and blocked by the @-adrenergic antagonist propranolol. Enhanced uptake did not appear an artifact of vesicle preparation as apparent vesicle sidedness, 4'Ca2+ efflux rates, specific activity of marker enzymes and equilibrium Ca2+ content were identical in vesicle preparations from control and 8-bromocyclic AMPtreated slices. Kinetic studies showed the ATP-dependent Ca2+ transport system in vesicles from B-bromocyclic AMP-treated slices displayed a-50% increase in Vmax and in K,,, Ca2+, compared to controls. The data suggest that physiological secretory stimuli to rat parotid acinar cells, which involve cyclic AMP, result in a readjustment of the basolateral membrane ATP-dependent Ca2+ pump. In nonexcitable mammalian tissues, plasma membrane ATP-dependent Ca2+ transport, presumably via a (Ca2+, Mg2+)-ATPase, constitutes the principal means of extruding Ca2+ against its steep electrochemical gradient (e.g. 1, 2). The
International Journal of Oral Surgery, Dec 1, 1984
Conservative and surgical methods are used to treat chronic dislocations of the temporomandibular... more Conservative and surgical methods are used to treat chronic dislocations of the temporomandibular joint. Different techniques described in the literature are discussed. 8 cases treated by eminectomy are presented and the results are evaluated.
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Papers by Joseph Helman