Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.

BACKGROUND: Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. RESULTS: In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. CONCLUSIONS: Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.

Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.

Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compare the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Given changes to treatment regimens and differences in length of follow-up, two treatment periods were defined a priori: 2000-2010 and 2011-2018. The SMR of patients treated during the period 2000-2010 and who survived one year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI: 3.20-5.21), and 8.62 (95% CI: 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMR were 2.89 (95% CI: 1.54-4.94), 3.12 (95% CI: 1.90-4.82), and 4.75 (95% CI: 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by five years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after ten years and after five years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond five years to be comparable to that of the general US population.

Protocol for indirect and direct co-culture between human cancer cells and endothelial cells.

The cross talk between cancer cells and endothelial cells (ECs) within the tumor microenvironment plays a critical role in tumor progression, recurrence, and cancer stemness. Here, we present a protocol containing two in vitro approaches to study such interactions. We first describe an indirect co-culture system to study the regulation of stemness markers in cancer cells by secreted factors from ECs. We then detail a direct co-culture system to study juxtracrine communications between the cell types. For complete details on the use and execution of this protocol, please refer to Sewell-Loftin et al.1 and Guo et al.2.

Hemophilia orthopedic management with emphasis on developing countries.

The articular problems of patients with hemophilia begin in infancy when minor injuries result in hemarthroses. Early continuous prophylaxis (from cradle to college) is of paramount importance because the immature skeleton is very sensitive to the complications of hemophilia; severe structural deficiencies may develop quickly. If continuous prophylaxis is not feasible owing to the expense of the clotting material or lack of venous access, then a major hemarthrosis must be treated aggressively to prevent the development of synovitis, recurrent joint bleeds, and ultimately end-stage arthritis. Once synovitis has developed, which bleeding will make inevitable, the aim should be to treat it as soon as possible. There are conservative (synoviorthesis) and operative (open or arthroscopic synovectomy) methods. Between the second and fourth decades, many patients with hemophilia develop articular complications. Once this has occurred, treatment modalities such as alignment osteotomies, joint debridement, arthrodesis, and arthroplasties are possible. Should surgery be required, one should consider multiple procedures.

The unfavorable nature of preoperative delirium in elderly hip fractured patients.

The onset of delirium is frequent in elderly patients who sustain hip fractures. The purpose of this study was to characterize different patterns of preoperative and postoperative delirium, to study factors associated with preoperative delirium and to evaluate the possible different outcome of these patients. This retrospective study comprised 281 elderly patients with hip fractures undergoing surgical fixation. Data collection included age, sex, length of stay, type of fracture, cognitive status by mini mental state examination (MMSE), assessment of possible delirium by the confusion assessment method (CAM) and functional outcome assessed by functional independence measure (FIM). A database search was conducted to identify whether delirium onset occurred prior to or following surgery. About 31% of the total sample developed delirium. Delirious patients tended to be more disabled (P = 0.03) and cognitively impaired (P = 0.018), compared with non-delirious patients. Most delirious cases (53%) had their onset in the preoperative period. Patients with preoperative delirium were older (P = 0.03), had a lower prefracture mobility (P < 0.01), impaired cognition (P = 0.04) and showed an adverse functional outcome in terms of FIM score. Regression analysis showed that prefracture dementia, prefracture mobility and low MMSE scores were strongly associated with higher probability of having preoperative delirium, with no additional effect of other variables. It is concluded that preoperative delirium should be viewed as a separate entity with unfavorable nature and adverse outcome. Careful preventive measures and better treating strategies should be employed to avoid this clinical condition.

Nonoperative treatment of intracapsular fractures of the proximal femur.

Of 2776 intracapsular fractures of the proximal femur, 18% of the patients were treated nonoperatively. Included in the group of patients who were treated conservatively were children, patients with cardiac problems or mental problems, stroke, renal failure, multiple disseminated malignancies, and patients who chose nonoperative treatment. The medical treatment protocol can be divided into two stages: Initially, (1) nursing of a bedridden patient with emphasis on the prevention of complications; and (2) once partial bone union has occurred, the attempted rehabilitation to independent ambulation. Paramedical services provide a major contribution during inpatient therapy and during the preparation for returning the patient to the community. A multidisciplinary medical team evaluates and assesses the patient's needs and rehabilitation potential and in cooperation with the patient and the family, an operative plan then is established.

Meperidine analgesia and delirium in aged hip fracture patients.

Delirium is quite frequent in elderly patients who sustain hip fractures. The use of Meperidine by physicians, unaware of the possible emergence of delirium in elderly patients, is very popular. We have retrospectively examined the incidence of delirium in 181 consecutive patients admitted to the orthogeriatric ward with hip fractures. We used the confusion assessment method to establish the presence of delirium in all patients. A database search was conducted to identify which patients were treated by Meperidine, or Morphine, prior to delirium onset. We identified 92 cases, 44 of whom were treated by Meperidine alone, and the other 48 treated by Morphine alone. Delirium was diagnosed in 13 (27.1%) Morphine treated patients as compared with 19 (43.2%) treated by Meperidine (P<0.001). Age, cognitive status and opiate use were associated with perioperative delirium. A subset regression analysis showed that exposure to Meperidine was significantly associated with delirium (odds ratio 2.5, P<0.01), in contrast with Morphine. Our results confirm the association between exposure to Meperidine and delirium, suggesting that this drug should be withdrawn in elderly hip fractured patients undergoing surgery, and substituted by low dose Morphine analgesia. Reducing the incidence of delirium, by adopting such an approach, may result in a significant potential of savings in direct costs, related to treatment of delirium in this population.