Urinary exosomes-based Engineered Nanovectors for Homologously Targeted Chemo-Chemodynamic Prostate Cancer Therapy via abrogating EGFR/AKT/NF-kB/IkB signaling.

Multi-functional nanovectors based on exosomes from cancer cell culture supernatants in vitro has been successfully utilized for tumor-specific targeting and immune escape. However, the labor-intensive purification procedures for rich-dose and high-purity homogeneous exosomes without using targeting ligands are still a challenging task. Herein, we developed a nanovector Exo-PMA/Fe-HSA@DOX through cloaked by urinary exosome membrane as a chemo/chemodynamic theranostic nano-platform for targeted homologous prostate cancer therapy which pertain to the abrogation of Epidermal Growth Factor Receptor (EGFR) and its downstream AKT/NF-kB/IkB signaling instead of ERK signaling cascades. Urinary exosomes-based nanovectors own the same urological cancer cell membrane antigen inclusive of E-cadherin, CD 47 and are free from intracellular substance such as Histone 3 and COX Ⅳ. The targeting properties of the homologous cancer cell are well preserved in Exo-PMA/Fe-HSA@DOX nanovectors in high purity. Meanwhile, the nanovectors based on urinary exosomes from prostate patients deeply penetrated into prostate cancer DU145 3D MCTS, and successfully achieve superior synergistic low-dose chemo/chemodynamic performance in vivo. In addition, the blockage of bypassing EGFR/AKT/NF-kB/IkB signaling pathway is greatly enhanced via elevated intracellular PMA/Fe-HSA@DOX nanoparticles (NPs). It is expected that the rich source and high purity of urinary exosomes offer a reliable solution for mass production of such nanovectors in the future. The targeted homologous cancer therapy based on the urinary exosomes from cancer patients exemplifies a novel targeted anticancer scheme with efficient and facile method.

Effects of immersive virtual reality therapy on intravenous patient-controlled sedation during orthopaedic surgery under regional anesthesia: A randomized controlled trial.

BACKGROUND: Immersive virtual reality (IVR) is a form of distraction therapy that has shown potential as an analgesia and sedation sparing agent. This study assessed the effect of IVR on the self-administered sedation requirements of patients undergoing joint replacement surgery under regional anesthesia in a single center. METHODS AND FINDINGS: This study was a single-center, randomized control trial at St Vincent's Hospital in Melbourne, Australia. Fifty patients undergoing elective total knee and total hip arthroplasty were randomized to IVR and Propofol patient-controlled sedation (PCS) or propofol PCS alone. The primary outcome measure was intra-operative propofol use. Secondary outcomes included pattern of propofol use over time, use of adjunct analgesia, unmet propofol demand, and patient satisfaction survey scores. Of 50 total patients, 25 received IVR in conjunction with PCS, and 25 received PCS alone. All patients received adjunct analgesia from the treating Anesthesiologist. Median propofol use/hour over the entire procedure in the control group was 40 (11.1, 93.9) mg/hour compared with 45 (0, 94.7) mg/hour in the IVR group (p = 0.90). There were no differences in patterns of propofol use over the course of each procedure. Adjusting for various baseline characteristics did not change the results. Postoperative satisfaction scores were equivalent in both groups. The VR intervention was well tolerated by all patients, with no report of major side effects. Key limitations were relatively small sample size, the non-blinded nature of the study, and use of adjunct analgesia. CONCLUSIONS: In patients receiving joint replacement surgery under regional anesthesia with PCS, IVR was well tolerated but did not decrease the overall sedation requirement.

Passion fruit-like exosome-PMA/Au-BSA@Ce6 nanovehicles for real-time fluorescence imaging and enhanced targeted photodynamic therapy with deep penetration and superior retention behavior in tumor.

Exosomes (Exos) of approximately 30-150 nm in diameters are the promising vehicles for therapeutic drugs. However, several challenges still exist in clinical applications, such as unsatisfied yield of exosomes, complicated labeling procedure and low drug loading efficiency. In this work, the gram-scale amount of high-purity urinary exosomes can be obtained from gastric cancer patients by non-invasive method. Passion fruit-like Exo-PMA/Au-BSA@Ce6 nanovehicles were fabricated by considerable freshly-urinary Exos loaded efficiently with multi-functionalized PMA/Au-BSA@Ce6 nanoparticles via instant electroporation strategy. In this system, prepared Exo-PMA/Au-BSA@Ce6 nanovehicles could be internalized into cancer cells effectively, and could delay the endocytosis of macrophages and prolong blood circulation time owing to its membrane structure and antigens. Under 633 nm laser irradiation and acidic condition, the structures of nanovehicles would be collapsed and tremendous PMA/Au-BSA@Ce6 nanoparticles could be released inside cancer cells, produced considerable singlet oxygen, inhibiting growth of tumor cells. In vivo experiment of MGC-803 tumor-bearing nude mice showed that prepared Exo-PMA/Au-BSA@Ce6 nanovehicles could target tumor cells with deep penetration and superior retention performance in tumors. This work reports a reliable conjugation-free labeling strategy for tracking exosomes harvested from human urine. Moreover, the integration of multifunctional nanoparticles with urinary Exos paves a versatile road for the development of cancer-targeted photodynamic therapy.

Cancer Rehabilitation: Do Functional Gains Relate to 60 Percent Rule Classification or to the Presence of Metastasis?

BACKGROUND: Literature supporting the benefits of inpatient rehabilitation for cancer patients is increasing. Many cancer patients, however, do not qualify for inclusion in the Centers for Medicare and Medicaid 60% rule and consequently may not receive services. The benefit of inpatient rehabilitation in this specific cancer group has not been investigated and is the focus of this study. OBJECTIVE: To investigate functional gains made during inpatient rehabilitation by patients impaired by cancer, and to compare the functional gains made during inpatient rehabilitation for patients impaired by cancer in relation to the presence or absence of metastatic disease and compliance or noncompliance with the Medicare 60% rule. SETTING: Freestanding university-affiliated rehabilitation hospital. PARTICIPANTS: A total of 176 adult patients admitted for inpatient rehabilitation due to cancer. METHODS: Retrospective chart review of patients admitted for inpatient rehabilitation with deficits identified related to cancer. MAIN OUTCOME MEASURES: Demographic data including cancer type, presence of metastasis, age, gender, marital status, ethnicity, length of stay (LOS), discharge destination, and transfer to acute care. Functional status including admission and discharge Functional Independence Measure Score (FIM), total, motor, and cognitive FIM gains, total, motor, and cognitive FIM efficiency for the study sample, for patients with and without a diagnosis compliant with the 60% rule and for patients with and without metastatic disease. RESULTS: In all, 176 cases met inclusion criteria. An admission coded diagnosis that was compliant with the 60% rule was present in 97 cases (55.1%). In 153 cases, the presence or absence of metastatic disease was known. Metastatic disease was present in 69 cases (45%). All groups (total sample, metastatic versus nonmetastatic, compliant versus noncompliant) made significant functional gains. Patients with a diagnosis noncompliant with the 60% rule had higher admission total FIM (P = .001), discharge total FIM (P = .014), admission motor FIM (P = .005), admission cognitive FIM (P = .008), and discharge cognitive FIM (P < .001) scores than those with a compliant diagnosis. Patients with metastatic disease had higher admission total FIM (P = .026) and admission (P = .001) and discharge (P = .02) cognitive FIM scores than patients with nonmetastatic disease. There were no significant differences between groups regarding total, motor, or cognitive FIM gains or total motor or cognitive FIM efficiencies. Differences in age, length of stay, and admission motor and discharge FIM scores between groups were related to cancer types and source of impairment. CONCLUSION: Patients with functional limitations resulting from cancer or its treatment made significant functional gains in inpatient rehabilitation. There were no significant differences in functional gains made by those with or without metastatic disease or those compliant versus noncompliant with the 60% rule. The presence of metastatic disease or a diagnosis not compliant with the 60% rule does not preclude cancer patients from making significant functional gains.

Update on Brain Tumors: New Developments in Neuro-oncologic Diagnosis and Treatment, and Impact on Rehabilitation Strategies.

Brain tumors can be a source of functional impairment to patients due to neurologic sequelae associated with the tumor itself as well as treatment side effects. As a result, many of these patients may require rehabilitation services. Surgery, chemotherapy, and radiation therapy have been longstanding, primary treatment modalities in the management of brain tumors, though these treatments continue to evolve given new developments in research and technology. A better understanding of the diagnostic workup and current treatment standards helps the physiatrist and rehabilitation team identify rehabilitation services needed, recognize potential side-effects from anticipated or concurrent treatments, and coordinate care with referral sources. The purpose of this article is to review these new advances in diagnosis and treatment of patients with brain tumors, as well as discuss the rehabilitation implications for this population, including factors such as rehabilitation approach, timing of concomitant treatment, cost management, and coordination of care.

Pediatric Acute Hematogenous Osteomyelitis.

BACKGROUND: Osteomyelitis continues to be a significant problem among the New Zealand pediatric population. We present a large series of acute hematogenous osteomyelitis (AHO) cases, with the aim to identify any changing trends and guide successful management of the disease. METHODS: A 10-year retrospective review was performed of clinical records of children with AHO at the 2 children's orthopaedic departments in the Auckland region. Cases were identified from Starship Children's Hospital between 1997 and 2007 and Middlemore's Kidz First Hospital between 1998 and 2008. RESULTS: A total of 813 cases of pediatric AHO were identified. The incidence was 1:4000, which was decreasing over the 10-year period. There was a male predominance and New Zealand (NZ) Maori and Pacific Islanders were overrepresented. The diagnosis was made clinically in 27%, radiographically in 66%, and surgically in 7%. The most common pathogen was Staphylococcus aureus and the incidence of methicillin-resistant S. aureus was low (2%). The average length of antibiotic treatment was 44 days and 44% required surgery. This produced a recurrence rate of only 7% and a 15% treatment-related complication rate. CONCLUSIONS: In the New Zealand population, the incidence of AHO remains high with NZ Maori and Pacific Islanders overrepresented. The predominant pathogen remains S. aureus and our population has a very low incidence of methicillin-resistant S. aureus; flucloxacillin remains a good choice for empiric treatment in our population. Our rate of relapse and subsequent chronic osteomyelitis is low. This could be explained by traditionally longer antibiotic courses; however, this may also lead to increased treatment-related complications. Through prompt and accurate diagnosis with the aid of laboratory and radiologic tests and effective treatment with appropriate antibiotics (guided by local pathogen sensitivities) and surgical treatment when indicated, AHO can be well managed with minimal severe complications. LEVEL OF EVIDENCE: Level IV-retrospective case series.

Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.

Effective treatment as well as prognostic biomarker for malignant esophageal squamous cell carcinoma (ESCC) is urgently needed. The present study was aimed at identifying oncogenic genes involving dysregulated intracellular Ca2+ signaling, which is known to function importantly in cellular proliferation and migration. Tumors from patients with ESCC were found to display elevated expression of Orai1, a store-operated Ca2+ entry (SOCE) channel, and the high expression of Orai1 was associated with poor overall and recurrence-free survival. In contrast to the quiescent nature of non-tumorigenic epithelial cells, human ESCC cells exhibited strikingly hyperactive in intracellular Ca2+ oscillations, which were sensitive to treatments with Orai1 channel blockers and to orai1 silencing. Moreover, pharmacologic inhibition of Orai1 activity or reduction of Orai1 expression suppressed proliferation and migration of ESCC in vitro and slowed tumor formation and growth in in vivo xenografted mice. Combined, these findings provide the first evidence to imply Orai1 as a novel biomarker for ESCC prognostic stratification and also highlight Orai1-mediated Ca2+ signaling pathway as a potential target for treatment of this deadly disease.

How 'preventable' are lower extremity amputations? A qualitative study of patient perceptions of precipitating factors.

PURPOSE: Clinicians commonly believe that lower extremity amputations are potentially preventable with coordinated care and motivated patient self-management. We used in-depth interviews with recent amputees to assess how patients viewed their initial amputation risk and causes. METHOD: We interviewed 22 patients at a rehabilitation hospital 2-6 weeks after an incident amputation. We focused on patients' representations of amputation cause and methods of coping with prior foot and leg symptoms. RESULTS: Patients reported unexpected onset and rapid progression of ulceration, infection, progressive vascular disease, foot trauma and complications of comorbid illness as precipitating events. Fateful delays of care were common. Many had long histories of painful prior treatments. A fatalistic approach to self-management, difficulties with access and communication with providers and poor understanding of medical conditions were common themes. Few patients seemed aware of the role of smoking as an amputation risk factor. CONCLUSIONS: Most patients felt out of control and had a poor understanding of the events leading to their initial amputations. Prevention of subsequent amputations will require rehabilitation programs to address low health literacy and psychosocial obstacles to self-management.

TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway.

TIEG1 can induce apoptosis of cancer cells, but its role in inhibiting invasion and metastasis has not been reported and is unclear. In this study, we find that decreased TIEG1 expression is associated with increased human epidermal growth factor receptor (EGFR) expression in breast cancer tissues and cell lines. TIEG1 plays an important role in suppressing transcription of EGFR by directly binding to the EGFR promoter. While overexpression of TIEG1 attenuates EGFR expression, knockdown of TIEG1 stimulates EGFR expression. Furthermore, TIEG1 and HDAC1 form a complex, which binds to Sp1 sites on the EGFR promoter and inhibits its transcription by suppressing histone acetylation. TIEG1 significantly inhibits breast cancer cell invasion, suppresses mammary tumorigenesis in xenografts in mice, and decreases lung metastasis by inhibition of EGFR gene transcription and the EGFR signaling pathway. Therefore, TIEG1 is an antimetastasis gene product; regulation of EGFR expression by TIEG1 may be part of an integral signaling pathway that determines and explains breast cancer invasion and metastasis.

Inpatient rehabilitation of patients with cancer: efficacy and treatment considerations.

Although cancer can affect a great number of individuals and is the second leading cause of death in the United States, the number of individuals admitted to acute inpatient rehabilitation units with impairments primarily as the result of cancer diagnoses remains small. There is a lack of awareness among health care providers as to the functional loss that can be associated with cancer and the potential benefits of inpatient rehabilitation. Furthermore, financial pressures from third-party payors may dissuade the admission of patients with cancer for inpatient rehabilitation. This is a narrative review of the literature with respect to the efficacy and potential benefits of inpatient rehabilitation for patients with cancer. The findings of studies on the rehabilitation of general cancer populations are presented, with a focus on functional outcomes, medical complications and transfer rates, and common symptoms encountered during inpatient rehabilitation. Studies that focus on tumors involving the brain and spinal cord are separately analyzed. Functional outcomes by tumor location are reviewed with respect to tumor type, recurrence, and comparison with nontumor diagnoses. In addition, the effects of concomitant treatments on functional outcomes and possible correlations of survival with functional outcome are presented. Justification for admission of patients with cancer diagnoses to inpatient rehabilitation units, as well as implications for management of these patients during their rehabilitation stay, will be summarized.

Pediatric calcaneal osteomyelitis.

BACKGROUND: Osteomyelitis continues to be a common problem amongst the pediatric population. Osteomyelitis of the calcaneus is an uncommon problem that still poses a problem to the treating physician. The purpose of this article is to retrospectively review a large series of pediatric patients with calcaneal osteomyelitis. We compare our experience with that in the literature to determine any factors that may aid earlier diagnosis and or improve treatment outcomes. METHODS: A 10-year retrospective review was performed of clinical records of all cases of pediatric calcaneal osteomyelitis managed at the 2 children's orthopaedic departments in the Auckland region. The Osteomyelitis Database was used to identify all cases between 1997 and 2007, at Starship Children's Hospital, and 1998 and 2008 at Middlemore's Kids First Hospital. RESULTS: Sixty patients fulfilled the inclusion criteria, and had a review of clinical notes and relevant investigations. The average duration of symptoms before presentation to hospital was 6.8 days. About 40% of patients had a recent episode of trauma. About 82% of patients could not bear weight on admission. Only 22% of patients had a temperature above 38°C. Erythrocyte sedimentation rate was elevated in 81% and the C-reactive protein was elevated in 77% of patients. About 27% of patients had positive blood cultures with Staphylococcus aureus being the most commonly cultured organism. X-rays, bone scans, and magnetic resonance imaging were all used to aid the diagnosis. About 20% of patients had surgery with an average of 1.3 surgeries for those who progressed to surgery. Treatment length was an average of 2 weeks 6 days of intravenous antibiotics followed by 3 weeks 2 days of oral treatment. There were no postsurgical complications and 10 readmissions: 3 for relapse, 3 for peripherally inserted central catheter line problems, and 4 for antibiotic-associated complications. CONCLUSIONS: Although sometimes more difficult to diagnose, calcaneal osteomyelitis can be diagnosed with an appropriate history, clinical examination, and investigations. Treatment with intravenous and oral antibiotics and surgical debridement if indicated can lead to a good clinical outcome with minimal complications.

Massive recurrent anterior diaphragmatic hernia, coronary artery disease, and valvular heart disease.

We report the case of a 76-year-old woman found on preoperative evaluation for vaginal prolapse to have coronary artery disease, aortic stenosis, and a large recurrent anterior diaphragmatic hernia. The clinical presentation and surgical management of this case, and the review of the literature are discussed.