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Mysite Group

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Carlos Breinholt
Carlos Breinholt

Ls 242-243 - Google Drive

Ls 242-243 - Google Drive -

Several lines of evidence establish a role of chronic BCR-mediated signaling in CLL pathogenesis [127]. (i) Prognosis is correlated with the BCR SHM status [128]; (ii) The BCR repertoire is highly restricted [129, 130], suggesting a role for antigenic selection in the initiation or progression of CLL. Antigens binding to CLL BCRs include self-antigens, such as non-muscle myosin IIA, vimentin, apoptotic cells and oxidized low-density lipoprotein [131,132,133,134,135,136], as well as foreign antigens (bacterial polysaccharides and β-(1,6)-glucan, a major antigenic determinant on fungi [132,133,134,135,136,137]); Interestingly, evidence was provided in mice that pathogens may drive CLL pathogenesis by selecting and expanding pathogen-specific B cells that cross-react with self-antigens [138]; (iii) CLL cells were reported to display cell-autonomous Ca2+ mobilization in the absence of exogenous ligands, by virtue of recognizing a single conserved BCR-internal epitope in the IGHV second framework region [139]; very recently, it was found that the internal epitopes recognized by CLL BCRs from distinct subgroups are different [140]. Moreover, the avidity of the BCR-BCR interactions that can lead to receptor declustering influences the clinical course of the disease [139, 140].

Besides the several potential and alleged indications of PPIs in cancer patients, increasing evidence suggests, for this class of drugs, an anti-tumor effect (through the selective induction of apoptosis as well as an anti-inflammatory effect) [344]. They also exert a protection of cancer cells from developing chemo- or radiotherapeutic resistance [345]. Acidification of the extracellular compartment represents a conceivable mechanism of drug resistance in malignant cells. In addition, it drives proliferation and promotes invasion and metastasis [345]. Experimental evidence has shown that PPIs counteract tumor acidification (via inhibition of vacuolar H+ ATPase) and restore sensitivity to anticancer drugs. Moreover, early clinical data have supported their role as add-on medications to anticancer treatments in patients with osteosarcoma or breast cancer [346]. A recent large epidemiological study (the SPORE program [347]) found that patients with head and neck tumors, taking acid suppressants, had significantly longer overall survival compared to those who did not. Specifically designed clinical trials are ongoing to better characterize the role of PPIs as new therapeutic agents in cancer treatment. Therefore, at the current status of present knowledge, PPI use as adjunct to cancer chemotherapy should not be performed outside a clinical trial.

A systematic review, performed in 2008, was unable to find any randomized clinical trials on acid-lowering drugs in the prevention of esophago-gastric variceal bleeding in cirrhotic patients. It is therefore not possible to establish whether these drugs are beneficial or harmful in this setting [350]. It is worth mentioning, however, that PPI use is associated with a microbiota shift and functional changes in the distal gut of patients with compensated cirrhosis, an effect that could drive or aggravate the pre-existing small intestine bacterial overgrowth [351, 352].

Examples of high power-to-weight ratios can often be found in turbines. This is because of their ability to operate at very high speeds. For example, the Space Shuttle's main engines used turbopumps (machines consisting of a pump driven by a turbine engine) to feed the propellants (liquid oxygen and liquid hydrogen) into the engine's combustion chamber. The original liquid hydrogen turbopump is similar in size to an automobile engine (weighing approximately 352 kilograms (775 lb)) and produces 72,000 hp (54 MW)[2] for a power-to-weight ratio of 153 kW/kg (93 hp/lb).

Power-to-weight ratios for vehicles are usually calculated using curb weight (for cars) or wet weight (for motorcycles), that is, excluding weight of the driver and any cargo. This could be s


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