Karthik Pittala | University of Michigan (original) (raw)
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Papers by Karthik Pittala
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Journal of Gastrointestinal Surgery
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Peptides, 2021
The structural conservation and activity of the myosuppressin cardioinhibitory peptide across spe... more The structural conservation and activity of the myosuppressin cardioinhibitory peptide across species suggests it plays an important role in physiology, yet much remains unknown regarding its signaling. We previously reported Drosophila melanogaster myosuppressin (dromyosuppressin, DMS; TDVDHVFLRF-NH2) decreases cardiac contractility through a G protein-coupled receptor, DMS-R2. Our study showed the DMS N-terminus amino acids influence its structure-activity relationship (SAR), yet how they act is not established. We predicted myosuppressin N-terminal amino acids played a role in activity and signaling. Here, we tested our hypothesis in the beetle, Zophobas atratus, using a semi-isolated heart bioassay to explore SAR in a different Order and focus on cardiac signaling. We generated a series of myosuppressin truncated analogs by removing the N-terminal residue and measuring the activity of each structure on cardiac contractility. While DVDHVFLRF-NH2 decreased cardiac contractility, we found VDHVFLRF-NH2, DHVFLRF-NH2, and HVFLRF-NH2 increased activity. In contrast, VFLRF- NH2 decreased activity and FLRF-NH2 was inactive. Next, we analyzed molecular docking data and found the active truncated analogs interacted with the 3-6 lock in DMS-R2, the myosuppressin cardiac receptor, disrupting the salt bridge between H114 and E369, and K289 and Q372. Further, the docking results showed the inhibitory effect on contractility may be associated with contact to Y78, while the analogs that increased contractility lacked this interaction. The data from our study demonstrated N-terminal amino acids played a role in myosuppressin activity and signaling suggesting the cardiac receptor can be targeted by biased agonists. Our myosuppressin cardiac contractility data and predicted receptor interactions describe the presence of functional selectivity in a ligand-directed signaling pathway in heart.
Cureus
Ovarian cancer is a feared diagnosis for women and clinicians alike. Ovarian mucinous adenocarcin... more Ovarian cancer is a feared diagnosis for women and clinicians alike. Ovarian mucinous adenocarcinoma is a unique subset of ovarian cancer. As a primary tumor, massive ovarian masses, and more specifically mucinous adenocarcinomas, have been infrequently reported in the medical literature. Team approaches to massive tumor extirpations are essential, as patients often require the expertise of various subspecialists including, but not limited to, gynecologic-oncologists, general surgeons, and plastic and reconstructive surgeons. Here we present a case of a 71-year-old woman with a massive, incapacitating pelvic mass, later found to be a primary ovarian mucinous adenocarcinoma. Once medically optimized, a multi-service team approach was utilized for tumor extirpation and abdominal wall reconstruction. Involved surgical services included Gynecologic-Oncology, General Surgery, and Plastic and Reconstructive Surgery. Exploratory laparotomy for tumor extirpation, hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal stripping, bilateral inguinal lymphadenectomy, and appendectomy was performed. Extensively thin, devascularized, and attenuated abdominal wall fascia that was adherent to the tumor was removed. The abdominal wall defect was reconstructed and reinforced with inlay and overlays of biologic monofilament mesh. Inverted-T of the vertical and horizontal skin components was performed in a tailortacking fashion, assuring the maintenance and protection of the abdominal skin flap vascularity through utilizing the Huger Zones of perfusion. Pathology revealed a stage IA grade 2 mucinous adenocarcinoma of the ovary without evidence of metastasis. No adjuvant therapies were required. The tumor's weight was 140 pounds, and its dimensions were 63 x 41 x 40 cm. It is our hope that presenting this experience will raise awareness of this spectrum of diseases and allow for earlier diagnoses and treatments, as well as exemplify the virtues of a team-based approach in the successful extirpation and subsequent reconstruction of the abdominal wall and skin.
Frontiers in Oncology
Multimodality therapy including surgical resection is the current paradigm in treating malignant ... more Multimodality therapy including surgical resection is the current paradigm in treating malignant pleural mesothelioma (MPM), a thoracic surface cancer without cure. The main limitation of all surgical approaches is the lack of long-term durability because macroscopic complete resection (R1 resection) commonly predisposes to locoregional relapse. Over the years, there have been many studies that describe various intrapleural strategies that aim to extend the effect of surgical resection. The majority of these approaches are intraoperative adjuvants. Broadly, there are three therapeutic classes that employ diverse agents. The most common, widely used group of adjuvants are comprised of direct therapeutics such as intracavitary chemotherapy (± hyperthermia). By comparison, the least commonly employed intrathoracic adjuvant is the class comprised of drug-device combinations like photodynamic therapy (PDT). But the most rapidly evolving (new) class with much potential for improved effica...
JAMA Network Open
IMPORTANCE Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrom... more IMPORTANCE Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome are associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. OBJECTIVE To characterize the outcomes of lung neuroendocrine tumors associated with Cushing syndrome. DESIGN, SETTING, AND PARTICIPANTS An observational case series review from 1982 to 2020 was conducted in a single institution referral center. Kaplan-Meier analysis estimated disease-free survival (DFS). Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. EXPOSURES Lobectomy or pneumonectomy vs sublobar resection. MAIN OUTCOMES AND MEASURES Disease-free survival, disease persistence/recurrence. RESULTS Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 [70.6%]), followed by wedge resection (16 of 68 [23.5%]) and segmentectomy (3 of 68 [4.4%]). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median DFS was reached in 12.7 years (0.1-334 months). There were no statistical differences in DFS based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. CONCLUSIONS AND RELEVANCE In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors.
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Journal of Gastrointestinal Surgery
Journal of neurological surgery. Part B, Skull base, Feb 1, 2024
Peptides, 2021
The structural conservation and activity of the myosuppressin cardioinhibitory peptide across spe... more The structural conservation and activity of the myosuppressin cardioinhibitory peptide across species suggests it plays an important role in physiology, yet much remains unknown regarding its signaling. We previously reported Drosophila melanogaster myosuppressin (dromyosuppressin, DMS; TDVDHVFLRF-NH2) decreases cardiac contractility through a G protein-coupled receptor, DMS-R2. Our study showed the DMS N-terminus amino acids influence its structure-activity relationship (SAR), yet how they act is not established. We predicted myosuppressin N-terminal amino acids played a role in activity and signaling. Here, we tested our hypothesis in the beetle, Zophobas atratus, using a semi-isolated heart bioassay to explore SAR in a different Order and focus on cardiac signaling. We generated a series of myosuppressin truncated analogs by removing the N-terminal residue and measuring the activity of each structure on cardiac contractility. While DVDHVFLRF-NH2 decreased cardiac contractility, we found VDHVFLRF-NH2, DHVFLRF-NH2, and HVFLRF-NH2 increased activity. In contrast, VFLRF- NH2 decreased activity and FLRF-NH2 was inactive. Next, we analyzed molecular docking data and found the active truncated analogs interacted with the 3-6 lock in DMS-R2, the myosuppressin cardiac receptor, disrupting the salt bridge between H114 and E369, and K289 and Q372. Further, the docking results showed the inhibitory effect on contractility may be associated with contact to Y78, while the analogs that increased contractility lacked this interaction. The data from our study demonstrated N-terminal amino acids played a role in myosuppressin activity and signaling suggesting the cardiac receptor can be targeted by biased agonists. Our myosuppressin cardiac contractility data and predicted receptor interactions describe the presence of functional selectivity in a ligand-directed signaling pathway in heart.
Cureus
Ovarian cancer is a feared diagnosis for women and clinicians alike. Ovarian mucinous adenocarcin... more Ovarian cancer is a feared diagnosis for women and clinicians alike. Ovarian mucinous adenocarcinoma is a unique subset of ovarian cancer. As a primary tumor, massive ovarian masses, and more specifically mucinous adenocarcinomas, have been infrequently reported in the medical literature. Team approaches to massive tumor extirpations are essential, as patients often require the expertise of various subspecialists including, but not limited to, gynecologic-oncologists, general surgeons, and plastic and reconstructive surgeons. Here we present a case of a 71-year-old woman with a massive, incapacitating pelvic mass, later found to be a primary ovarian mucinous adenocarcinoma. Once medically optimized, a multi-service team approach was utilized for tumor extirpation and abdominal wall reconstruction. Involved surgical services included Gynecologic-Oncology, General Surgery, and Plastic and Reconstructive Surgery. Exploratory laparotomy for tumor extirpation, hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal stripping, bilateral inguinal lymphadenectomy, and appendectomy was performed. Extensively thin, devascularized, and attenuated abdominal wall fascia that was adherent to the tumor was removed. The abdominal wall defect was reconstructed and reinforced with inlay and overlays of biologic monofilament mesh. Inverted-T of the vertical and horizontal skin components was performed in a tailortacking fashion, assuring the maintenance and protection of the abdominal skin flap vascularity through utilizing the Huger Zones of perfusion. Pathology revealed a stage IA grade 2 mucinous adenocarcinoma of the ovary without evidence of metastasis. No adjuvant therapies were required. The tumor's weight was 140 pounds, and its dimensions were 63 x 41 x 40 cm. It is our hope that presenting this experience will raise awareness of this spectrum of diseases and allow for earlier diagnoses and treatments, as well as exemplify the virtues of a team-based approach in the successful extirpation and subsequent reconstruction of the abdominal wall and skin.
Frontiers in Oncology
Multimodality therapy including surgical resection is the current paradigm in treating malignant ... more Multimodality therapy including surgical resection is the current paradigm in treating malignant pleural mesothelioma (MPM), a thoracic surface cancer without cure. The main limitation of all surgical approaches is the lack of long-term durability because macroscopic complete resection (R1 resection) commonly predisposes to locoregional relapse. Over the years, there have been many studies that describe various intrapleural strategies that aim to extend the effect of surgical resection. The majority of these approaches are intraoperative adjuvants. Broadly, there are three therapeutic classes that employ diverse agents. The most common, widely used group of adjuvants are comprised of direct therapeutics such as intracavitary chemotherapy (± hyperthermia). By comparison, the least commonly employed intrathoracic adjuvant is the class comprised of drug-device combinations like photodynamic therapy (PDT). But the most rapidly evolving (new) class with much potential for improved effica...
JAMA Network Open
IMPORTANCE Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrom... more IMPORTANCE Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome are associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. OBJECTIVE To characterize the outcomes of lung neuroendocrine tumors associated with Cushing syndrome. DESIGN, SETTING, AND PARTICIPANTS An observational case series review from 1982 to 2020 was conducted in a single institution referral center. Kaplan-Meier analysis estimated disease-free survival (DFS). Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. EXPOSURES Lobectomy or pneumonectomy vs sublobar resection. MAIN OUTCOMES AND MEASURES Disease-free survival, disease persistence/recurrence. RESULTS Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 [70.6%]), followed by wedge resection (16 of 68 [23.5%]) and segmentectomy (3 of 68 [4.4%]). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median DFS was reached in 12.7 years (0.1-334 months). There were no statistical differences in DFS based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. CONCLUSIONS AND RELEVANCE In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors.