University of Miami Miller School of Medicine
Recent publications
Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare and life-threatening disorder that usually occurs in patients with end-stage renal disease (ESRD) and less frequently in non-uremic patients [1–3]. The term calciphylaxis, first coined by Dr. Seyle in 1961, literally means “protection by calcification.” Dr. Seyle described calciphylaxis in rats as an adaptive (phylatic) response that leads to calcium deposition in the affected tissues [4]. In 1963, Eisenberg and Bartholow reported a case of extensive metastatic calcification in a patient with chronic renal failure, which represented the human counterpart of calciphylaxis [5]. Over the course of the following years several cases of calciphylaxis have been described [6–10].
To understand how the nucleosome remodeling and deacetylase (NuRD) complex regulates enhancers and enhancer–promoter interactions, we have developed an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule trajectories. Unexpectedly, this has revealed that NuRD binds to chromatin for minutes, decompacts chromatin structure and increases enhancer dynamics. We also uncovered a rare fast-diffusing state of enhancers and found that NuRD restricts the time spent in this state. Hi-C and Cut&Run experiments revealed that NuRD modulates enhancer–promoter interactions in active chromatin, allowing them to contact each other over longer distances. Furthermore, NuRD leads to a marked redistribution of CTCF and, in particular, cohesin. We propose that NuRD promotes a decondensed chromatin environment, where enhancers and promoters can contact each other over longer distances, and where the resetting of enhancer–promoter interactions brought about by the fast decondensed chromatin motions is reduced, leading to more stable, long-lived enhancer–promoter relationships.
Histone lysine methylation is a major epigenetic modification that participates in several cellular processes including gene regulation and chromatin structure. This mark can go awry in disease contexts such as cancer. Two decades ago, the discovery of histone demethylase enzymes thirteen years ago sheds light on the complexity of the regulation of this mark. Here we address the roles of lysine demethylases JMJD3 and UTX in physiological and disease contexts. The two demethylases play pivotal roles in many developmental and disease contexts via regulation of di- and trimethylation of lysine 27 on histone H3 (H3K27me2/3) in repressing gene expression programs. JMJD3 and UTX participate in several biochemical settings including methyltransferase and chromatin remodeling complexes. They have histone demethylase-dependent and -independent activities and a variety of context-specific interacting factors. The structure, amounts, and function of the demethylases can be altered in disease due to genetic alterations or aberrant gene regulation. Therefore, academic and industrial initiatives have targeted these enzymes using a number of small molecule compounds in therapeutic approaches. In this chapter, we will touch upon inhibitor formulations, their properties, and current efforts to test them in preclinical contexts to optimize their therapeutic outcomes. Demethylase inhibitors are currently used in targeted therapeutic approaches that might be particularly effective when used in conjunction with systemic approaches such as chemotherapy.
Diving animals must sustain high activity with limited O2 stores to successfully capture prey. Studies suggest that increasing body O2 stores supports breath-hold diving, but less is known about metabolic specializations that underlie underwater locomotion. We measured maximal activities of 10 key enzymes in locomotory muscles (gastrocnemius and pectoralis) to identify biochemical changes associated with diving in pathways of oxidative and substrate-level phosphorylation and compared them across three groups of ducks—the longest diving sea ducks (eight spp.), the mid-tier diving pochards (three spp.) and the non-diving dabblers (five spp.). Relative to dabblers, both diving groups had increased activities of succinate dehydrogenase and cytochrome c oxidase, and sea ducks further showed increases in citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HOAD). Both diving groups had relative decreases in capacity for anaerobic metabolism (lower ratio of lactate dehydrogenase to CS), with sea ducks also showing a greater capacity for oxidative phosphorylation and lipid oxidation (lower ratio of pyruvate kinase to CS, higher ratio of HOAD to hexokinase). These data suggest that the locomotory muscles of diving ducks are specialized for sustaining high rates of aerobic metabolism, emphasizing the importance of body O2 stores for dive performance in these species.
Herein, the phase partitioning of triton X-100 (TX-100) and ceftriaxone sodium trihydrate (CTS) drug mixture in aqueous solutions of sodium salts was thoroughly investigated. The sodium carbonate (Na2CO3), sodium nitrate (NaNO3), sodium oxalate (Na2C2O4), and sodium phosphate (Na3PO4) were used to explore the effect of sodium salts on the cloudy creation of the mixture of TX-100 and applied drug. The CTS is a broad-spectrum cephalosporin antibiotic drug that is extensively utilized to cure bacterial diseases. The CP values of employed system were attained to be lessened by increasing the concentration of sodium salts (Na salts) and followed the pattern: \({\text{CP}}_{{{\text{aq}}.{\text{ NaNO}}_{3} }} > {\text{CP}}_{{{\text{aq}}.{\text{ Na}}_{3} {\text{PO}}_{4} }} > {\text{CP}}_{{{\text{aq}}.{\text{ Na}}_{2} {\text{CO}}_{3} }} > {\text{CP}}_{{{\text{aq}}.{\text{ Na}}_{2} {\text{C}}_{2} {\text{O}}_{4} }} .\) The estimated several thermodynamic entities (\(\Delta G_{c}^{0}\), \(\Delta H_{c}^{0}\), and \(\Delta S_{c}^{0}\)) change of phase partitioning of TX-100 + CTS drug is the measurement of interactions that exist between TX-100 and CTS in aquatic Na-salts environments. The calculated (\(\Delta G_{c}^{0}\)) values were positive in the studied inspections, which demonstrated the nonspontaneous process of phase partitioning for the investigating system in aq. Na-salts media. The enthalpy–entropy compensation variables associated with the clouding process of TX-100 + CTS mixture in H2O + salts media were also calculated and interpreted in a detailed way. The operating forces between TX-100 and CTS are electrostatic and hydrophobic, which is evident from the values of \(\Delta H_{c}^{0}\) and \(\Delta S_{c}^{0}\).
Introduction/Background In patients who respond to neoadjuvant chemotherapy (NACT) for advanced-stage epithelial ovarian cancer (EOC), minimally invasive surgery (MIS) may reduce the morbidity of surgery. Studies evaluating oncologic outcomes of minimally invasive interval cytoreductive surgery are largely retrospective. Methodology LANCE is a prospective, multicenter, international, randomized trial evaluating whether MIS is non-inferior to laparotomy in terms of disease-free survival, among patients with stage IIIC and IV EOC with normalization of CA125 after 3–4 cycles of NACT. The planned 100 patients were enrolled in a lead-in phase to assess the feasibility of the trial with respect to cross-over among those assigned to MIS, complete gross resection, and recruitment. Patients were randomized (1:1) to undergo open or MIS (laparoscopic or robotic) surgery. Surgeons applied maximal effort to resect all visible tumor, conversion to open surgery was performed when necessary to attain complete resection.View this table: • View inline • View popup • Download powerpoint Abstract #236 Table 1 Demographic and clinical characteristics (n = 100) Results From September 2020-February 2023, 100 patients were randomized (51 open, 49 MIS). The mean age was 62 years, 67% had stage IIIC, and 54% received 3 cycles of NACT. Six patients randomized to MIS (12.2%;95%CI: 4.6–24.8%) underwent conversion to open surgery. Surgeons achieved complete gross resection in 87.5% (95%CI: 74.8–95.3%) and 83% (95%CI: 69.2–92.4%) of patients assigned to MIS and open (p=0.6). There were three (6.3%) intraoperative complications in the MIS group and three (6.4%) in the open group. Two patients (4.1%) in the MIS group experienced grade 4–5 adverse events following surgery. Conclusion Evaluation of MIS interval cytoreductive surgery is feasible, enrollment is ongoing in a definitive trial.
Background Liposarcoma is the most commonly diagnosed subtype of soft tissue sarcoma. As these tumors often arise near vital organs and neurovascular structures, complete resection can be challenging; consequently, recurrence rates are high. Additionally, available chemotherapeutic agents have shown limited benefit and substantial toxicities. There is, therefore, a clear and unmet need for novel therapeutics for liposarcoma. Discoidin domain receptor tyrosine kinase 1 (DDR1) is involved in adhesion, proliferation, differentiation, migration, and metastasis in several cancers. However, the expression and clinical importance of DDR1 in liposarcoma are unknown. Questions/purposes The purposes of this study were to assess (1) the expression, (2) the association between DDR1 and survival, and (3) the functional roles of DDR1 in liposarcoma. Methods The correlation between DDR1 expression in tumor tissues and clinicopathological features and survival was assessed via immunohistochemical staining of a liposarcoma tissue microarray. It contained 53 samples from 42 patients with liposarcoma and 11 patients with lipoma. The association between DDR1 and survival in liposarcoma was analyzed by Kaplan-Meier plots and log-rank tests. The DDR1 knockout liposarcoma cell lines were generated by CRISPR-Cas9 technology. The DDR1-specific and highly selective DDR1 inhibitor 7RH was applied to determine the impact of DDR1 expression on liposarcoma cell growth and proliferation. In addition, the effect of DDR1 inhibition on liposarcoma growth was further accessed in a three-dimensional cell culture model to mimic DDR1 effects in vivo. Results The results demonstrate elevated expression of DDR1 in all liposarcoma subtypes relative to benign lipomas. Specifically, high DDR1 expression was seen in 55% (23 of 42) of liposarcomas and no benign lipomas. However, DDR1 expression was not found to be associated with poor survival in patients with liposarcoma. DDR1 knockout or treatment of 7RH showed decreased liposarcoma cell growth and proliferation. Conclusion DDR1 is aberrantly expressed in liposarcoma, and it contributes to several markers of oncogenesis in these tumors. Clinical Relevance This work supports DDR1 as a promising therapeutic target in liposarcoma.
Background People with substance use disorders are vulnerable to acquiring HIV. Testing is fundamental to diagnosis, treatment, and prevention; however, in the past decade, there has been a decline in the number of substance use disorder (SUD) treatment programs offering on-site HIV testing. Fewer than half of SUDs in the USA offer on-site HIV testing. In addition, nearly a quarter of newly diagnosed cases have AIDS at the time of diagnosis. Lack of testing is one of the main reasons that annual HIV incidences have remained constant over time. Integration of HIV testing with testing for HCV, an infection prevalent among persons vulnerable to HIV infection, and in settings where they receive health services, including opioid treatment programs (OTPs), is of great public health importance. Methods/design In this 3-arm cluster-RCT of opioid use disorders treatment programs, we test the effect of two evidence-based “practice coaching” (PC) interventions on the provision and sustained implementation of on-site HIV testing, on-site HIV/HCV testing, and linkage to care. Using the National Survey of Substance Abuse Treatment Services data available from SAMHSA, 51 sites are randomly assigned to one of the three conditions: practice coach facilitated structured conversations around implementing change, with provision of resources and documents to support the implementation of (1) HIV testing only, or (2) HIV/HCV testing, and (3) a control condition that provides a package with information only. We collect quantitative (e.g., HIV and HCV testing at 6-month-long intervals) and qualitative site data near the time of randomization, and again approximately 7–12 months after randomization. Discussion Innovative and comprehensive approaches that facilitate and promote the adoption and sustainability of HIV and HCV testing in opioid treatment programs are important for addressing and reducing HIV and HCV infection rates. This study is one of the first to test organizational approaches (practice coaching) to increase HIV and HIV/HCV testing and linkage to care among individuals receiving treatment for opioid use disorder. The study may provide valuable insight and knowledge on the multiple levels of intervention that, if integrated, may better position OTPs to improve and sustain testing practices and improve population health. Trial registration NCT03135886. Registered on 2 May 2017.
Purpose: To evaluate coagulation necrosis depth (CND) of Holmium (HL), Moses (ML), and Thulium fiber laser (TFL) in ex vivo human prostate tissue at various energy settings. Methods: After endoscopic HL enucleation, small prostate tissue fragments were removed from the bladder with graspers and used for study. Immediately after surgery, a single incision was made on the surface of the tissue kept under normal saline at room temperature using a hand-held 550-µm laser fiber. Variable energy settings were tested for all three lasers. Two pathologists measured the CND with light microscopy using ocular micrometer. Impact of various laser settings on CND was analyzed. The differences in CND of all three lasers at similar laser power were compared. Results: Mean CND was 0.56 ± 0.53 mm for long-pulse HL, 0.54 ± 0.53 mm for ML, 0.67 ± 0.67 mm for low-pulse TFL, and 0.81 ± 0.78 mm for high-pulse TFL. There was no significant difference between mean CND of HL and ML at various laser settings ranging from 10 to 120 W and CND with long- and short-pulse settings of TFL at settings from 10 to 60 W. There was a trend of increasing CND in HL and ML with increasing laser power; however, it was not statistically significant. TFL had similar tissue effects as HL and ML. Conclusion: There is no significant difference in CND of HL, ML, and TFL in ex vivo human prostate tissue. Other factors besides laser type and settings need to be studied to explain clinical differences among various lasers used for prostate enucleation.
Background: Recent advancements in supermicrosurgery and promising preliminary outcomes have led to a surge in physiologic lymphedema surgery. This study is the first to evaluate lymphedema surgical education among United States plastic surgery residency programs, along with the background and experience of plastic surgeons subspecializing in the field. Methods: Cross-sectional evaluation of 103 accredited United States plastic surgery residency programs was performed in January 2023. Web-based searches of program curricula, faculty profiles, and main institutional pages indicated whether a program provided nonclinical or clinical exposure to lymphedema surgery. Review of online faculty profiles, surname searches, Doximity, and Scopus determined the perceived demographics, academic productivity, and procedures performed by lymphedema surgeons. Results: Compared to the 11 programs that incorporated lymphedema surgery into their online curriculum, 67 programs had a rotation site with a surgeon performing lymphedema procedures. Of the 33 programs without evidence of clinical exposure, 76% (n=25) did not provide or specify providing elective time. Faculty perceived to be female or a race underrepresented in plastic surgery had significantly more assistant professor titles (p<0.0214) and significantly fewer years of experience (p<0.0293) than their counterparts. Conclusion: Great variation in lymphedema surgical education exists among US plastic surgery residency programs. While few programs incorporate lymphedema surgery into their advertised curriculum, programs without clinical exposure frequently did not provide elective time to obtain it. Faculty that were female or a race underrepresented in plastic surgery were most often early in their career, suggesting lymphedema surgeons may grow increasingly diverse in years to come.
Background: Cryoanalgesia is a tool being used by interventional radiology to treat chronic pain. Within a certain cold temperature range, peripheral nerve function is interrupted, and recovers, without neuroma formation. Cryoanalgesia has most often been applied to the intercostal nerve. Cryoanalgesia has applications to peripheral nerve surgery, yet is poorly understood by reconstructive microsurgeons. Methods: Histopathology of nerve injury was reviewed to understand cold applied to peripheral nerve. Literature review was performed utilizing the PubMed and MEDLINE databases to identify comparative studies of the efficacy of intraoperative cryoanalgesia versus thoracic epidural anesthesia following thoracotomy. Data was analyzed using Fisher’s Exact and ANOVA tests. A similar approach was used for pudendal cryoanalgesia. Results: Application of inclusion and exclusion criteria resulted in 16 comparative clinical studies of intercostal nerve for this review. For thoracotomy, nine studies compared cryoanalgesia to pharmaceutical analgesia, with seven demonstrating significant reduction in postoperative opioid use or postoperative acute pain scores. In these nine studies, there was no association between the number of nerves treated and the reduction in acute post-operative pain. One study compared cryoanalgesia to local anesthetic and demonstrated a significant reduction in acute pain with cryoanalgesia. Three studies compared cryoanalgesia to epidural analgesia and demonstrated no significant difference in postoperative pain or postoperative opioid use. Interventional radiology targets pudendal nerves using CT-imaging with positive outcomes for the patient with pain of pudendal nerve origin. Conclusions: Cryoanalgesia is a term used for the treatment of peripheral nerve problems that would benefit from a proverbial reset of peripheral nerve function. It does not ablate the nerve. Intraoperative cryoanalgesia to intercostal nerves is a safe and effective means of postoperative analgesia following thoracotomy. For pudendal nerve injury, where an intrapelvic surgical approach may be difficult, cryoanalgesia may provide sufficient clinical relief, thereby preserving pudendal nerve function.
The potential effects of artificial intelligence (AI) on the teaching of anatomy are unclear. We explore the hypothetical situation of human body donors being replaced by AI human body simulations and reflect on two separate ethical concerns: first, whether it is permissible to replace donors with AI human body simulations in the dissection room when the consequences of doing so are unclear, and second, the overarching ethical significance of AI use in anatomy education. To do this, we highlight the key benefits of student exposure to the dissection room and body donors, including nontechnical, discipline‐independent skills, awareness and interaction with applied bioethics, and professional identity formation. We suggest that the uniqueness of the dissection room experience and the importance of the key benefits accompanying this exposure outweigh the potential and so far unknown benefits of AI technology in this space. Further, the lack of engagement with bioethical principles that are intimately intertwined with the dissection room experience may have repercussions for future healthcare professional development. We argue that interaction with body donors must be protected and maintained and not replaced with AI human body donor simulations. Any move away from this foundation of anatomy education requires scrutiny. In light of the possible adoption of AI technologies into anatomy teaching, it is necessary that medical educators reflect on the dictum that the practice of healthcare, and anatomy, is a uniquely human endeavor.
Regular exercise is known to positively impact neurocognitive health, particularly in aging individuals. However, low adherence, particularly among older adults, hinders the adoption of exercise routines. While neuroplasticity mechanisms largely support the cognitive benefits of exercise, the link between physiological and behavioral factors influencing exercise adherence remains unclear. This study aimed to explore this association in sedentary middle-aged and older adults. Thirty-one participants underwent an evaluation of neuroplasticity using transcranial magnetic stimulation (TMS) to measure changes in motor-evoked potentials following intermittent theta-burst stimulation (iTBS). Health history, cardiorespiratory fitness, and exercise-related behavioral factors were also assessed. The participants engaged in a 2-month supervised aerobic exercise program, attending sessions three times a week for 60 minutes each, totaling 24 sessions at a moderate-to-vigorous intensity. They were divided into Completers (n=19), who attended all sessions, and Dropouts (n=12), who withdrew early. Completers exhibited lower smoking rates, exercise barriers, and resting heart rates compared to Dropouts. For Completers, regression models revealed that post-iTBS changes (β= -7.78, p= .013) and self-efficacy (β= −.51, p= .019) predicted exercise adherence (adjusted-R2= 0.44). Larger post-iTBS increases in motor-evoked potential amplitude indicated greater effectiveness of cortico-motor plasticity and were associated with better exercise adherence. In conclusion, this study highlights the significance of cortico-motor plasticity, self-efficacy, and cardiovascular health in exercise adherence. Given the well-established cognitive benefits of exercise, addressing sedentary behavior and enhancing self-efficacy are crucial for promoting adherence and optimizing brain health. Clinicians and researchers should prioritize assessing these variables to improve the effectiveness of exercise programs.
The introduction of digital imaging and planning tools in dentistry has dramatically changed the traditional workflow and greatly expanded the range of treatment options available for patients with total or near-total edentulism. Although the placement of dental implants is the standard of care for restoring lost dentition, many edentulous patients were not candidates for this treatment in the past because alveolar resorption following tooth loss left them with inadequate bone to support them. Studies have shown that wearing removable dentures can reduce patients’ quality of life, causing pain and areas of discomfort, chewing and speaking difficulties, slippage, reduced occlusal force, and poor oral sensation. In contrast to conventional removable dentures, full-arch implant rehabilitation utilizing a digital workflow is a predictable treatment with less morbidity, less laboratory and clinical chair-time, and a substantial increase in patient satisfaction.
The term facial rejuvenation refers to several different categories of treatments designed to improve the appearance of the face: plastic surgery such as rhinoplasty, blepharoplasty, and rhytidectomy; less invasive procedures such as dermal abrasions and chemical peels; and the growing list of minimally invasive therapies, including laser skin resurfacing, microdermabrasion, neurotoxin injections, and dermal filler injections. Dermal fillers are administered in a very short timeframe and have immediate results. This chapter explores the benefits of using dermal fillers and different methods regarding facial rejuvenation that support aesthetic procedures and correlate with positive results.
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Mahendra Singh
  • Sylvester Comprehensive Cancer Center
Alex Mechaber
  • Division of General Internal Medicine
Paolo Serafini
  • Department of Microbiology and Immunology
Fardous El-Senduny
  • Department of Pathology
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Henri R. Ford, M.D., MHA