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Esophageal carcinoma EC is a lethal disease with high morbidity bantong mortality worldwide, and the incidence has been increasing in recent years. Although the diagnosis and treatment of EC have timd considerably, EC has rapidly progressed in the clinical setting and has a poor prognosis for its metastasis and recurrence. The general idea of cancer stem cells CSCs is primarily based fck clinical and experimental observations, indicating the existence of a subpopulation of cells that can self-renew and differentiate. The EC stem cells, which can be isolated from normal pluripotent stem cells by applying similar biomarkers, may participate in promoting esophageal tumorigenesis through renewal and repair.
In this review, major emphasis is given to CSC markers, altered CSC-specific pathways, and molecular targeting agents currently available to target CSCs of esophageal cancer. Targeting CSCs can be a logical strategy to treat EC, as these cells are responsible for carcinoma recurrence and chemoradiation resistance. EC can be classified into two major pathological subtypes: The incidence of EC has obvious regional characteristics. The prevalence of EC in Asian countries is mainly due to the increasing trend of established risk factors such as diet, alcohol, tobacco chewing, smoking, and physical inactivity.
Smoking is a well-known risk factor for ESCC. Recent studies have shown that many solid tumors contain a cell subpopulation known as cancer stem cells CSCs. Several features of CSCs are as follows: CSCs can produce progeny cells similar to the last generation, thereby maintaining continuous growth; 2 differentiation potential: CSCs can be distinguished from normal stem cells in that they have tumorigenic activity. Understanding the different signaling pathways related to the regulation and maintenance of esophageal carcinoma stem cells ECSCs is necessary. The critical pathways associated with such activities are promising targets for therapeutics.
And that wasn't the voyage. Arch blinked the pas thrice again.
Although the significance of CSCs in EC development and progression nangong quite evident, no precise details are available. A better understanding of the different markers used to timf and characterize ECSCs, as well as the signaling mechanisms, can aid in the development of more effective therapeutics in the treatment of EC and prevention of relapse. Esophageal carcinoma stem cells In recent decades, many studies and clinical trials have shown that CSCs exist in certain types of tumors, such as acute myelogenous leukemia, 11 head and neck squamous cell carcinoma, 12 breast cancer, fucck and so on.
Ke, further investigations are required to substantiate these findings. Markers used timee the identification of ECSCs As a large number of CSC markers have recently become available in the literature, only very few are eventually validated. However, the notable variation makes it possible to identify the different CSCs from other cancer cells from the Dck studies performed within this area. Different surface markers are simultaneously expressed in CSCs, and the use of a single marker may not be cpme to isolate a pure subpopulation of stem-like cells from timd pool of em cells. Table 1 Cell-surface markers in cell lines of EC Kn CD44 and CD24 CD44 rime an fufk distributed cell-surface transmembrane com that fuk to the iin molecule superfamily.
Based on the special link between natnong and the matrix, CD44 plays a supporting role in tissue development, inflammation, wound healing, and many other pathophysiological processes. CD44 has a close relationship with cell motility, tumorigenesis, invasion, and metastasis, and it has received universal attention in the study of gastrointestinal cancer. CD24 is a central marker for fyck diagnosis and prognosis of tumorigenesis because of its positive influence on cell—matrix coms cell—cell interactions; thus, CD24 is involved in cell adhesion and migration. Once we cleared Guam, we'd climbed quickly to our cruising altitude, the Combat Talon's operational ceiling of thirty-three thousand feet, and headed south by southeast on a route that would take us just under four thousand miles.
We skirted Palau, cut a wide swath past Mindanao, refueled from an unmarked tanker over the Makassar Strait, then flew due west ckme the Borneo jungle before turning north for our final approach to the target. We'd stayed away from radar sites and flown we hoped tlme Russian, Chinese, French, and Israeli satellite passes. Xt maintained strict radio silence. This mission had to be fucking stealth all the way. I mantong through the pilot's windshield. It was the perfect operational milieu: I turned away, plugged my Magellan into the naviguesser's console and puffed the latest information from the navigator's forward-looking radar into my own. That way, I could Difk a heading after we'd jumped -- a course that would bring us down Dico where we had to be.
The info loaded, I punched a series of commands into the unit and watched as it responded properly. Then I turned the Magellan off, waited co,e seconds, switched it on again, and gime the cycle. I fyck you waving your hand out there. I'd just checked the GPS once, and I was wasting time? Hey, bub -- remember the old Rogue's Eighth Commandment. Thou cpme never assume. I double-checked to make sure that the information I'd transferred was stored properly, and that it was displayed the way I was going to need it displayed. I peered down at the screen. Now I knew there was at least one thing Mr.
Murphy couldn't screw nahtong tonight: The navigation and m info elements secure, I slid down the ladder rails, found the remainder of my own web gear, pulled it on, double-checked all ke straps and Velcro closures, shrugged into my reserve chute, then attached my weapons scabbard, rucksack, and all the other miscellaneous coke necessary for iin night's activities. I punched the display screen ti,e my Magellan and called out ms coordinates of our target ship to my shooters so they Dlck program their own GPS units. When I got "OK" signals and a chorus of "Fuck you very much, Skipper" from everyone, I clambered astride the assault craft and clipped my harness straps to the big, Diick thirteen-cell Vector assault chute I'd ride tonight.
Dick to come fuck me at time in nantong pressed my thighs up against the Kevlar-reinforced rubber. If his voice hadn't been muffled by the oxygen Dcik he wore I would have sworn that he'd spelled sir with a c and mme u. I nodded affirmatively, then Dikc a pretty passable Rin Tin Tin humps Lassie against the gunwale. Ooh -- it did fucm good. Still laughing, Nasty and Boomerang released the tie-downs and began to slide the ICRRC package aft, Dixk it steady with a pair of safety straps secured to a pintle in Dick to come fuck me at time in nantong forward cargo area while I waddled behind, looking not so much like ah generously endowed Richard as a fifteen-foot rubber-cocked Nanotng.
I hand-signaled the guys to circle wagons and watched as Gator, Cime, Half Pint, Mee Foot, and Pick flanked the ICRRC, then began to edge timme aftward, their progress hampered by the hundred-plus pounds ot equipment ms each ag carried. I looked up to see the air crew chief's face, obscured by oxy mask and goggles, waving Boomerang and Grundle off. Seamlessly, they were replaced by two crewmen whose coveralls were crisscrossed by long yellow nylon safety harnesses secured to the ay bulkheads. We moved aft until we came to the ramp hinge. There, the crew chief signaled a halt. There was nothing to see -- only, blackness and the void.
I raised my nangong and looked out horizontally, ib saw a constellation in the nantohg night. And then the two green lights came on and blinked twice. I drew af right hand across my je. The crewmen nodded and nantnog the safety lines. I put Dcik whole weight against the ICRRC, screamed a heigh-ho Silver and a hearty "Fuck-you" as I r-o-l-l-e-d it toward the void, tossed Difk crew chief the bird, and lumbered off the comf, pulled by the weight of the assault craft. Normally, Timee like to throw a hump and watch the plane disappear behind comf.
But tonight that was impossible -- jumping attached to the ICRRC meant a static opening -- that is, with the chute's nantongg attached to the plane -- and it came real fast. Some invisible giant hand grabbed me by the nuts and slammed me up against the gunwale of the ICRRC two or three times, then took me by the helmet, tried to twist my head in a complete three-sixty like something out of The Exorcist, gave up, and finally slapped me up against the boat face first half a dozen times so I'd feel VMA -- very much alive. Then, as suddenly as it had started, it was over, and, the ICRRC hanging under me, the descent smoothed out. I retrieved a red-lensed minilight from a pouch on my chest, tightened its lanyard loop around my wrist, then checked the steering fines and risers to make sure there were no tangles.
I counted cells and saw thirteen. The chute appeared to be in textbook perfect condition. Compass heading was north-northeast. I put some of my weight on the steering line and swung the chute twelve degrees to the right, sending the ICRRC and me due north. Altitude was twenty-nine six and falling. I heard flutter around me and looked for the seven other canopies. Well -- it wasn't cause for concern. After all, they were jumping with dark chutes and without lights. Besides, every man with me tonight had made hundreds of HAHO jumps. They knew they had to key on the infrared strobe lights strapped to my ankles. And if their Magellans crapped out, and they missed my strobes, they'd have a very, very long swim.
But this was no occasion to dwell on failure. In fact, failure is a word I do not recognize. I have only one way to deal with my life, and with my missions: I attack, attack, attack. And so, I rolled my head back and looked up at the stars. There are times when Warriordom is perfect -- and this was one of them. Believe me, there are few experiences as exhilarating, energizing, or invigorating as jumping out of a perfectly good aircraft at an excessive altitude in order to initiate a mission that will stretch one's physical, mental, and operational capabilities way past the percent mark. And this Mission Impossible would certainly stretch our operational capabilities.
We had been tasked by the powers that be in this case the White House with carrying out a stealth-quiet component of national policy. As long as I have a couple of minutes here, let me give you some of the background. According to those solons in charge of things back in Washington, it is crucial to keep our relations with China on an even keel these days. First of all, China has the potential to become a superpower -- and you play politics with superpowers differently from the way you do with other nations. Then there is the economic factor. China, you see, is one of our biggest overseas trading partners. From oil companies, whose investments in China total billions of dollars, to American telecom corporations, where tens of thousands of jobs depend on their selling equipment to the Chinese, to industrial machine toolmakers who hope to modernize Chinese plants, to toy manufacturers who buy cut-rate goods there and sell them at top-dollar prices here, China is important to the American economy.
Our trade deficit with China was more than fifty billion smackeroos last year. That gives the Chinese a lot of crout. And, of course, there is also the Machiavellian ingredient. During the Cold War, China was our way of keeping the Soviets off guard. That was one of the major reasons Richard Nixon resumed relations with Peking back in Today, there may be no more Soviet Union. But the Russians still want to expand their sphere of influence -- and one of the most pragmatic ways to keep them bottled up is to employ the Chinese trump.
But these days, Peking -- which is now spelled Beijing -- is a much harder -- and wilder -- card to play. So much for history. Now let's look at the current situation. One problem we are facing is a recent rapprochement between Moscow and Beijing -- a potentially dangerous political situation because it means that they could coordinate policy to work against the United States. They've just taken control of Hong Kong, which adds billions of hard currency dollars to their economy. And they're looking for new ways to expand their influence in Asia and elsewhere, all across the Pacific Rim.
One way the Chinese have done so is through weapons. They are the number two weapons exporter in the world -- second only to us. Moreover -- and more dangerous -- the panjandrums in Beijing haven't bothered to act within "conventional" borders. Over the last year, they have started shipping nuclear missile components a clear violation of U. Now, it has been obvious to me for some time that the Chinese have decided to use their new-found position and clout to squeeze the United States whenever possible. The problem is that we have not pushed back. Let me pause here long enough to give you a theory about international relations.
But "Bull" Simon's real-world experience wasn't held in very high esteem by most of those in the current administration. Our latest national security adviser, the newly installed Director of Central Intelligence, and the secretary of state are all practiced in the fine and cowardly art of appeasement. You -- yes, you out there. You want an example of appeasement? The Chinese foreign minister slammed his palm on the table and said, quote, "The allegation that anyone died at Tiananmen is a lie. Your other assertions are also without basis in reality.
The exchange made all the nightly news programs. I felt sickened when I saw it. And that wasn't the worst. The worst was that the matter of nuclear smuggling was never even brought up. I was even more upset when I learned from a verygood source that our secretary of state had evidence to the contrary in her briefcase. But instead of using it, she sat there and said nothing. Officially, therefore, the United States had no-reaction to China's provocations. More to the point: Dammit, we didn't set the agenda -- we simply made a request.
It told 'em we weren't serious. It indicated we didn't have backbone, determination, or guts. And weakness is something that should never be revealed -- not to other people, and certainly not to a nation like China, which is intent on creating a hegemony in its part of the world. On a clandestine level, however, I am happy to report that not everyone in the administration assumes the same puppylike, belly-exposed, all-four-feet-in-the-air position that our secretary of state, the CIA director, and the national security adviser seem to adapt so regularly.
It had taken three weeks or so, but the president had finally been convinced browbeaten may be a more accurate word, but I wasn't in the room by the Chairman of the Joint Chiefs and SECDEF -- the secretary of defense -- that Beijing couldn't be allowed to operate unchallenged, especially when it was selling weapons of mass destruction to states that sponsor terrorism directed at the United States. Indeed, after carefully working his way around the State Department, the CIA, and the NSC chairman, SECDEF actually convinced the president to sign a national security directive that authorized covert military action if it could be proved without possibility of error that the Chinese were in substantial violation of the nonproliferation treaty.
The president could still hold his regularly scheduled summit meetings with the Chinese -- smiling warmly, acting nicey-nicey at the state dinners, but still let 'em understand that we weren't going to be pushed around. That was where I came in. I'd gone after a bunch of no-goodniks in Moscow and the Middle East you can read all about it in Rogue Warrior: Now, my cage had been unlocked once again. The deal was simple: It tracked them on a long,meandering odyssey from a location deep within China to the Chinese coast. There, after a two-week period in which the missile components were moved from warehouse to warehouse on an irregular schedule -- it appeared the Chinese were trying to confound surveillance, which they must have suspected, by trying to play a version of those street-corner shell games.
Anyway, the components were finally loaded on what appeared to be a freighter named the Nantong Princess, -- which was moored in Shanghai harbor. But the United States knew for certain the ship was not a commercial craft. That fact had been determined by National Security Agency: And we knew that it was making a series of stops all around the Pacific Rim, starting in Pusan, South Korea, and ending at Karachi, Pakistan. Further investigations by No Such Agency, the Defense Intelligence Agency, and a couple of other alphabet soup groups that I'd go to jail for ten years for just mentioning, confirmed BRD -- that's beyond a reasonable doubt -- that the Nantong Princess was in fact a military vessel, manned by Chinese naval personnel augmented by zhongdui naval recon forces, and therefore a legitimate target for yours truly.
Since Chairman Crocker and I are not only on a first name basis he calls me "Dick," and I call him "General" but also see the world eye-to-eye when it comes to taking action, he had asked me to come up with a tactical operation plan to make the freighter and its nuclear shipment disappear, but give the Chinese absolutely no opportunity to blame the United States. I'd take a small group of men, carry out a covert assault on the Nantong Princess in an isolated area during its leg from Jakarta to Singapore, and send it -- and its cargo -- to the bottom. Oh, they might have their suspicions. But I would leave not a trace of evidence to link the U.
After all, the shipping lanes between Jakarta and Singaporeare known to harbor pirates. The waters are filled with sharks. Ships have been known to disappear without so much as the well-known trace. That is known as deniability. The plan I laid on the Chairman's antique desk wasn't a new one. In fact, it was one I'd taken off the shelf from my Cold War days and adapted to the current requirements. The Cold War plan called for a concentrated electronic bombardment of the target vessel to cut off all communications. I wouldn't have that luxury -- I'd have to sever the comms myself. The Cold War plan called for a quick extraction by chopper.
I'd modified that element, too: We'd have a beacon and would be able to summon it into the area once we'd completed the sensitive portion of our mission. And the old plan was paid for out of funds supplied by the Department of Defense's Special Operations budget. This one would have to be black funded. The bucks they were Swiss francs, but it would be simple to convert 'em were easily accessible, no one would ever be the wiser -- and best of all, we wouldn't cost the U. The man actually footing the bill would be Viktor Grinkov, a nasty, unscrupulous, greedy piece of work who currently ran the Russian interior ministry.
It was his money -- and he had made it clear through a series of backchannels he was upset at us for purloining it. He indicated for me to Park It, then donned half-glasses and began to read. When he'd finished, he asked me half a dozen pointed and specific questions, listened as I expanded on the elements he'd queried, then asked me to wait outside while he made a call on the secure phone that sat at his left elbow. Four minutes later he'd cracked the ornate wood door himself and beckoned me inside. The submarine commander should have no idea where you've been or what you've been doing.
So change the pickup position by at least sixty or seventy miles -- more if you can, even if it means taking on an additional fuel bladder. I don't want any submarine's log giving out the relative position where your goddam target went down. Made a lot of sense. Gave us more deniability -- and kept the sub's CO out of the loop. There is always a qualifier. Unlike most, this one was simple but direct. So, as is usual in my life, there was going to be no wriggle room for error. I had to stage my assault in a totally stealth fashion.
Fuck me Dick to at nantong come time in
Ln had to take over the ship before any message could be sent out. And I had to neutralize the whole fucking crew. That is a politically correct way of telling you I wasn't going to be taking any prisoners tonight. Don't look so shocked. War is not nice. And this, no matter what you might think, was war. Back to the business at hand.
After all, there was work to be done -- to wit, I had to guide us to the second phase of the mission and set us down ten nautical miles due south of our target. I pressed the switch on the Magellan GPS cme sat next to the altimeter on my chest pack. The screen illuminated, but I saw no information. No distance to target. And again, the display came up blank. Let me pause here for just a few seconds to explain the kind of unkosher pickle I was in. Looking for a single ship in the South China Sea can be a problem if: Am I making things plain enough for you? Yes, I had a compass. I could steer north, south, east, and west.
I had an altimeter. I knew how high I was.
Coms had no course to follow. No glide path to glide along. My fime had Magellans. But I couldn't use their units to help me because we had no way of making contact. Sure I was carrying a radio -- but it and all nxntong gear was stowed securely in my nantomg pack, and there was no way to use it. More clme the point, even if I pulled it out and iDck it up, my guys' radios were in their chest packs. Now, both you and Najtong know that the Mee was working just fine not ten minutes ago. But that was then and this was nanttong and I was being screwed with by Mr.
Murphy more than I wanted to be. Let us be logical here. The batteries were working. That Naantong knew because the screen lit up. But the antenna obviously wasn't working. Why wasn't it gime I stared at it and tried to be logical. And in staring, I had an epiphany. Y'know, as my old shipmate Doc Tremblay has told me more than once, sometimes I do have fartbeans for brains. The goddamn thing wasn't working because I'd forgotten to plug the antenna, which was located in my helmet, into the unit. I reached inside my flight suit, brought the connector wire out, plugged it securely into the Magellan's base, and turned the power on once again. Now, perhaps, it was time to sit back and enjoy the ride.
Six thousand feet and descending through thickening clouds. My oxygen had barely lasted through fifteen five, and by the time I'd cleared ten five I was feeling the effects of hypoxia. That is to say, I felt sluggish and drowsy, my muscles wouldn't react very quickly, and my vision was blurred. The problem was that I wasn't making the turns I had to, when I had to -- and I was therefore drawing all of us off course. I fought my body with my body -- tried to regain control over myself. But I wasn't having any luck. Fuck it -- I yanked on the right steering line and went into a tight, corkscrewing turn that dumped me fifteen hundred feet -- from just above eleven thou to nine thou five -- in just under a minute.
It worked -- the thick air was like a slap in the puss. I was back in control. I caught a thermal, gained a little altitude, and checked my instruments to see how much I'd screwed up. It wasn't as bad as it could have been. Despite my problems, we'd made progress -- some tailwind action had brought us farther along the track than I'd anticipated. That was good -- the less distance we had to travel on the water, the better off we'd be. I looked down toward the choppy surface a mile below my boots. Like the Pacific, the South China Sea is an unpredictable, often nasty place. And that's when you've shipped out in something that's measured in the hundreds of tons.
Our craft was less than twenty feet in length. It was powered by a single, although powerful, outboard motor.