Radiotherapy combined with chemotherapy after modified radical mastectomy decreases rates of locoregional and systemic relapse and reduces mortality from breast cancer.
For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.
Kinesin is a dimeric motor protein that transports organelles in a stepwise manner toward the plusend of microtubules by converting the energy of ATP hydrolysis into mechanical work. External forces can inf luence the behavior of kinesin, and force-velocity curves have shown that the motor will slow down and eventually stall under opposing loads of Ϸ5 pN. Using an in vitro motility assay in conjunction with a high-resolution optical trapping microscope, we have examined the behavior of individual kinesin molecules under two previously unexplored loading regimes: super-stall loads (>5 pN) and forward (plus-end directed) loads. Whereas some theories of kinesin function predict a reversal of directionality under high loads, we found that kinesin does not walk backwards under loads of up to 13 pN, probably because of an irreversible transition in the mechanical cycle. We also found that this cycle can be significantly accelerated by forward loads under a wide range of ATP concentrations. Finally, we noted an increase in kinesin's rate of dissociation from the microtubule with increasing load, which is consistent with a load dependent partitioning between two recently described kinetic pathways: a coordinated-head pathway (which leads to stepping) and an independent-head pathway (which is static).Kinesin is a homodimeric motor protein that uses the energy of ATP hydrolysis to transport organelles toward the plus-end of microtubules against the viscous drag of the cytoplasm. Each subunit consists of a Ϸ7 nm (Ϸ340 amino acid) globular motor domain (head) connected to a Ϸ75 nm (Ϸ500 amino acid) ␣-helical tail involved in dimerization (1). Like the motor proteins myosin and dynein, kinesin performs work by coupling a chemical ATPase cycle with a mechanical cycle resulting in an incremental movement and force production. Because kinesin is thought to operate alone or in small groups, it must be able to remain bound to the microtubule for numerous consecutive cycles before dissociating (termed processivity) to travel distances that are useful on a cellular length scale. The mechanism for coupling the ATPase and mechanical cycles, the directionality, the force generation event (power stroke), and the putative coordination between kinesin's two motor domains during processive movement all need to be elucidated to achieve a comprehensive understanding of kinesin function.Recent technological advances have opened the door to investigations of discrete nanometer-size movements and piconewton forces produced by individual motor molecules in vitro (2-5). This approach has proven fruitful in characterizing the stochastic behavior of kinesin. Studies have shown that kinesin moves in discrete steps along the microtubule (2, 6) and that it slows down linearly as a function of increasing load until it comes to a stall (5, 7-9). These studies have provided valuable information about the efficiency of the motor and the variability of its chemomechanical coupling. However, they are consistent with a variety of phenomenological mo...
Concurrent cisplatin may improve pelvic control of locally advanced bladder cancer with preoperative or definitive radiation, but has not been shown to improve overall survival. The use of concurrent cisplatin had no detectable effect on distant metastases.
What's known on the subject? and What does the study add?
Targeted agents have greatly changed the therapeutic landscape in RCC. A substantial number of trials have been published in recent years.
The current review summarises and analyses the available data to date.
OBJECTIVE
To estimate the effects of drugs with molecular targets on patients with advanced renal cell cancer (RCC).
PATIENTS AND METHODS
MEDLINE, EMBASE, and the Cochrane Collaboration Library were systematically searched on‐line through to June 2011 to identify eligible randomised trials. We also searched abstract reports from major oncology and urology meetings.
We included randomised trials that tested a targeted agent and reported at least one outcome by allocation on an intent‐to‐treat basis. Completeness of ascertainment and risk of bias were assessed.
Our primary outcome was progression‐free survival (PFS).
RESULTS
In all, 28 studies met our inclusion criteria and 10 were placebo‐controlled. Two studies were too small to assess, and five early studies used nonspecific anti‐angiogenic agents with poor activity. In all, 15 studies, in 5587 patients, tested anti‐vascular epithelial growth factor (VEGF) agents: bevacizumab (BEV), sorafenib, sunitinib, pazopanib, tivozanib, or axitinib. Three studies, in 1147 patients, tested the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus or everolimus. Two studies included epidermal growth factor receptor (EGFR) inhibitors, and one tested the combination of temsirolimus plus BEV.
In treatment‐naive patients with mostly good–moderate prognostic risk, in separate trials oral sunitinib (one trial) and intravenous BEV plus subcutaneousinterferon‐α (two trials) improved PFS compared with the previous standard of care interferon‐α within randomised phase III trials. Sorafenib did not improve PFS over interferon‐α in the first‐line setting and the addition of cytokines did not improve sorafenib efficacy. In poor‐risk patients, the mTOR inhibitor temsirolimus improved PFS and overall survival (OS). The studies of other VEGF inhibitors have used placebo controls no longer appropriate in this setting, although pazopanib is an approved option.
Several trials examined agents in the second‐line setting. After cytokine therapy, sorafenib (one study) and pazopanib (one study) prolonged PFS over placebo. A preliminary report of the investigational VEGF receptorinhibitor axitinib gave superior PFS to sorafenib after either prior cytokine or prior sunitinib treatment. After cancer progression ≤6 months of sunitinib and/or sorafenib therapy, everolimusprolonged PFS.
OS was marginally improved in several studies. A more substantial effect on OS may have been diluted by crossover from control therapy to the investigational arm and/or by other anti‐angiogenic agents after trial closure. Patient‐reported outcomes were considered unreliable in trials without ‘blinding’.
A clear cell RCC (ccRCC) component was required for most trials, and information for non‐ccRCCs is consequently limited
CONCLUSIONS
Agents targ...
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