We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin ...reductase; we now detail its effects in solid tumours.
Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells.
NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2-10 nM IC(50)s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho(0) cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation.
Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.
Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, ...participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long‐term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality‐of‐life assessment instruments, and cost‐benefit analyses.
This multicentric population-based study in Brazil is the first national effort to estimate the prevalence of hepatitis B (HBV) and risk factors in the capital cities of the Northeast, Central-West, ...and Federal Districts (2004-2005). Random multistage cluster sampling was used to select persons 13-69 years of age. Markers for HBV were tested by enzyme-linked immunosorbent assay. The HBV genotypes were determined by sequencing hepatitis B surface antigen (HBsAg). Multivariate analyses and simple catalytic model were performed. Overall, 7,881 persons were included; < 70% were not vaccinated. Positivity for HBsAg was less than 1% among non-vaccinated persons and genotypes A, D, and F co-circulated. The incidence of infection increased with age with similar force of infection in all regions. Males and persons having initiated sexual activity were associated with HBV infection in the two settings; healthcare jobs and prior hospitalization were risk factors in the Federal District. Our survey classified these regions as areas with HBV endemicity and highlighted the risk factors differences among the settings.
Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial ...proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy. The joints most commonly affected are the knees, elbows and ankles, although any synovial joint may be involved. In the ankle, both the tibiotalar and subtalar joints may be affected and joint bleeding and arthropathy can lead to a number of deformities. Haemophilic arthropathy can be prevented through regular factor replacement prophylaxis and implementing physiotherapy. However, when necessary, there are multiple surgical and non‐surgical options available. In early ankle arthropathy with absent or minimal joint changes, both radioisotopic and chemical synoviorthesis can be used to reduce the hypertrophied synovium. These procedures can decrease the frequency of bleeding episodes, minimizing the risk of articular cartilage damage. Achilles tendon lengthening can be performed, in isolation or in combination with other surgical measures, to correct Achilles tendon contractures. Both arthroscopic and open synovectomies are available as a means to remove the friable villous layer of the synovium and are often indicated when bleeding episodes cannot be properly controlled by factor replacement therapy or synoviorthesis. In the later stages of ankle arthropathy, other surgical options may be considered. Debridement may be indicated when there are loose pieces of cartilage or anterior osteophytes, and can help to improve the joint function, even in the presence of articular cartilage damage. Supramalleolar tibial osteotomy may be indicated in patients with a valgus deformity of the hindfoot without degenerative radiographic findings. Joint fusion, or arthrodesis, is the treatment of choice in the advanced stages of ankle arthropathy although total ankle replacement is currently available. Early ankle replacement components were associated with a poor outcome, but as implant designs have improved, there have been successful outcomes achieved. As the ankle is a commonly affected joint in many individuals with haemophilia, it is important to add to the knowledge base to validate indications and timing of surgical and non‐surgical interventions in ankle arthropathy.
Nonyrast, excited states in neutron-rich 186W were populated via inelastic-scattering reactions using beams of 136Xe nuclei accelerated to 725 and 800 MeV. Levels populated in the reactions were ...investigated via particle-γ coincidence techniques using the Gammasphere array of high-purity germanium detectors and the compact heavy-ion counter, CHICO2. The Kπ = 2+ (γ ), Kπ = 0+ and Kπ = 2– (octupole) rotational side bands were extended to spins 14h¯, 12h¯, and 13h¯, respectively. A staggering pattern observed in the energies of levels in the Kπ = 2+ band was found to be consistent with a potential that gets softer to vibration in the γ degree of freedom with increasing spin. Furthermore, the odd-even staggering of states in the Kπ = 2– band was found to exhibit a phase opposite to that seen in the γ band; an effect most probably associated with Coriolis coupling to other, unobserved octupole vibrational bands in 186W.
5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this ...combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC).
In this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate.
Eighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22-69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %).
FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A number of agents are now approved for the treatment of renal cancer. A comparison of two agents, pazopanib and sunitinib, showed similar levels of antitumor activity but distinct side-effect ...profiles. Symptoms affecting quality of life were somewhat worse with sunitinib.
Renal-cell carcinoma is the most common kidney cancer.
1
Up to 30% of patients have metastases at the time of the initial diagnosis.
2
Systemic treatment for patients who have metastatic renal-cell carcinoma with a clear-cell histologic component has shifted from cytokines to drugs targeting angiogenesis. Sunitinib, pazopanib, and five other agents have been approved by the Food and Drug Administration for the treatment of clear-cell, metastatic renal-cell carcinoma.
3
,
4
Among the tyrosine kinase inhibitors, pazopanib and sunitinib are first-line treatment options.
Sunitinib has been compared with interferon alfa in patients who had not previously received systemic therapy for renal-cell carcinoma,
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whereas . . .
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