CAR-T Cells in the Treatment of Chronic Lymphocytic Leukemia

CAR-T Cells in the Treatment of Chronic Lymphocytic Leukemia Abstract Cancer has always been a difficult problem to be solved by humans, of which leukemia is one of them. With the development of gene recombination technology and our in-depth understanding of cancer, chimeric antigen receptor T cells (CAR-T) can be carried out in clinical trials. Recently, CAR-T has made new progress in the treatment of acute and chronic lymphocytic leukemia. CAR-T cells are T-cell receptor gene and anti-CD19 antibody gene binding, transfection to T cells, in vitro amplification after transfer to patients for the treatment of leukemia new immunotherapy. The surface of the modified CAR-T cells has a specific binding site, which can recognize the CD19 antigen on the surface of B cells in lymphoblastic leukemia. CD19 antigen can stimulate the continuous activation and proliferation of CAR-T, CAR-T in the patients body can be multiplied hundreds of times, effectively killing acute and chronic lymphocytic leukemia cells. Keywords: car-t cell therapy, chronic lymphocytic leukemia 1. CAR-T principle With the development of gene recombination technology, the specific antibody can be stably expressed on the surface of T cells, so that it has a specific antigen epitope. Chimeric antigen receptor T cell immunotherapy is carried out on the basis of a cellular immunotherapy. The chimeric anti-gen receptor (CARs) is an antigen-recognition domain composed of a specific antibody in the extracellular domain and an antigen-chimeric protein composed of the intracellular CDC3-ÃŽ ¶ chain or FcÃŽ ³I protein linked to the transmembrane domain[1]. After the CARs are recognized and stimulated by specific antigens, they can provide activation signals for T cells and conduct the signals through the intracellular domain, which results in the activation of cells, which are CARs dependent cell activation and cytotoxicity, and cytokines Release [2]. In order to increase the cytotoxicity of CARs, the proliferation of signal transduction was achieved by constructing co-stimulatory molecules connected to the extracellular CD3CÃŽ ¶ in the intracellular domain, resulting in a multiplication of the cell killing effect, which greatly enhanced the CARs Cell killing effect [3]. Generation of CARs intracellular contains only one activation domain, so its specificity in the identification of tumor cell-associated antigens after killing effect is very limited [4]. Second-generation CARs contain an activation domain and a co-stimulatory domain, such as CD28 or 4-1BB [5-6]. The three-generation CARs are composed of the activation domain and multiple co-stimulatory domains, such as CD27, CD28, 4-1BB and OX40. The increase of these domains not only increases the ability of CAR-T cells to specifically recognize TAA and binding , More able to significantly extend the extracellular area of à ¢Ã¢â€š ¬Ã¢â‚¬ ¹Ãƒ ¢Ã¢â€š ¬Ã¢â‚¬ ¹the cell signal transmission, causing lower levels of cell killing cascade [7]. With the improvement of structural design of CARs and the improvement of tumor targeting and kil ling, the researchers have constructed many other intracellular co-stimulatory molecular structures, including CD134, Lck, ICOS and DAP10 [8]. In addition, CD19-derived CAR-T cells were further engineered by researchers at the Duke University Center for Immunology to autocrine IL-12, which may or may not be required in specific syngeneic tumor models Pretreatment chemotherapy, if further extended to clinical patients can be in the lower side effects to obtain better efficacy [9]. Therefore, the continuous innovation of CARs related technologies is not only the structural optimization, but also the construction of more costimulatory molecules in function. The efficiency and function of CAR-T cells will be further improved. 2. Obtain specific CAR-T cells CD19 is a potential target for B-cell neoplasms and can be expressed in normal B cells, follicular dendritic cells, malignant B cells, and precursor B cells in addition to hematopoietic stem cells [10]. Acute and chronic lymphocytic leukemia is usually accompanied by CD19 expression, but in other lymphoid system tumor expression is not the same. Jena and others through genetic modification technology for the first time applied to chronic viral vector, the CD19 + specific chimeric antigen receptorand expression of B cells, transfected into the patients T cells, the transformation of T cells called CD19-specific CAR -T cells [11]. These T cells in vitro after a large number of amplification, re-enter the acute and chronic lymphocytic leukemia patients play a role in the body. CD19-specific CAR-T cells are able to recognize leukemia specific CD19 targets and release B-cells from CD19 cells by releasing a variety of cytokines, thereby promoting the clearance of malignant tumor cells. The results show that, after retroviral gene transfection of T cells, in clinical applications is safe and effective [12]. CD19-specific CAR-T cells have been shown to be effective in attacking CD19 + tumor cell lines and in vivo B-cell tumors in animals [13]. In immunodeficient mice, CD19 + T cells can be effectively removed by the addition of CD19 + T cells [14]. 3. CAR-T cells in the treatment of chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a slow-growing, inert B-cell leukemia, usually occurring in adults, and many patients can have no symptoms for several years, compared with other types of leukemia. Currently CLL has no specific treatment options, no obvious symptoms of CLL advocates observation and wait, mainly symptomatic treatment, drug therapy is difficult to achieve long-term remission and clinical cure. Genetically modified CAR-T cells have a significant therapeutic effect on B-cell malignancies. The New England Journal reported in June that the June Task Force [15] successfully treated 3 patients with CLL with CAR-T cells for the first time, 2 of whom were still in complete remission after 2 years of follow-up. They subsequently found that [16], the infusion of CAR-T cells in patients with peripheral blood and bone marrow in a large number of survival, proliferation in the body more than 1000 times, effective removal of CLL cells function can be maintained for more than 6 months. Not only that, some CAR-T cells are even in the form of memory cells that produce a rapid response when re-exposed to CLL cells. The mechanisms by which CAR-T cells proliferate and survive in vivo are unclear, probably due to the activation or release of cytokines by normal B cells and CD19-expressing leukemic cells in the internal environment. The cytokines such as IFN-r, CXCL9, IL-6 and soluble IL-2 receptor increased significantly after CAR-T cells entered the body, reaching a peak on the 23rd day after transfusion. Elevated cytokines in bone marrow were consistent with reduced levels of leukemic cells, but TNF levels in peripheral blood and bone marrow did not vary significantly. The number of CAR-T cells in vivo was detected by RT-PCR, and the ratio of cells increased 1000-fold on the 21st day after transfection, accounting for more than 20% of the peripheral blood lymphocytes. The number of CAR-T cells was consistent with the time of oncolytic syndrome and elevated lev els of cytokines. The doubling time of CAR-T cells in peripheral blood was about 1.2 days and the half-life was 31 days. It is noteworthy that cytotoxic side effects such as cytokine release syndrome and macrophage activation syndrome may occur after treatment with CAR-T cell immunotherapy. These symptoms and children hemophagocytic syndrome, lymphoproliferative disease occurs in similar cytokine storm [17]. Cytokine storm is due to CAR-T cells kill B cells caused by tumor cell lysis, characterized by inflammation, long-term fever, hepatosplenomegaly, cell reduction. At this point the laboratory examination of patients with ferritin, triglyceride, transaminase, bilirubin, soluble IL-2 receptor a chain were increased and fibrinogen reduction [18]. CAR-T cells after the input, the patients peripheral blood and bone marrow loss of B cells and hypogammaglobulinaemia up to 6 months or more, but patients do not necessarily have recurrent infection. If the clinical symptoms require symptom atic treatment, the number of CAR-T cells in the patients body or the anti-tumor effect will not be significantly affected. In the past, patients treated with rituximab, after a few months of treatment, B cells can gradually pick up. Whether this phenomenon will occur in patients with CAR-T cell immunotherapy is still unclear. Because CAR-T cells can proliferate extensively and produce cytotoxicity in vivo, CAR-T cell-specific detection is needed in the course of clinical treatment [19], and timely prevention of adverse reactions occurs. 4. Adverse reactions and treatment Although CAR-T cell therapy has achieved surprising clinical results, but have to admit that there are still many cell treatment process risk, adverse reactions after treatment for the treatment of a great test. Because CAR-T can proliferate in vivo and produce severe cytotoxic effects on target cells, the most common and serious is cytokine release syndrome (CRS) [20]. In the current report of CAR-T cells in the treatment of blood cancer cases, almost all appeared in different severity of the CRS response. CRS is mainly due to the large number of cells after activation, including circulating IL-6, ferritin, INFÃŽ ³, IL-2, granulocyte colony stimulating factor IL-10, IL-8, IL-5, including rapid increase in cytokines Caused by fever without cause of infection, persistent hypotension, and even reports of neurological toxicity such as seizures [21-22]. CRS was observed in 48 of the 51 patients treated with CD19-modified CAR-T cells (94%) and serum ferritin levels were greater than 1000 mg / dl in all patients with severe CRS 4-5 C The relationship between the increase of CRP and the course of disease was similar to that of ferritin, but serum C reactive protein and ferritin level did not have significant effect on the prediction of CRS progression. Further, they used 10 healthy volunteers as baseline and found that severe CRS responses within 1 month after CAR-T cell therapy were associated with 24 cytokines including IFNÃŽ ³, IL-6, SGP-130, and SIL6R Serum levels of the peak correlation [23]. Patients with severe CRS response to the survival of patients posed a huge risk, patients with severe hypotension or shock, respiratory distress syndrome, neurotoxicity, liver and kidney dysfunction, it must actively deal with the situation. In addition to the use of vasoactive drugs, tracheotomy and enhanced supportive therapy, the application of IL-6 receptor inhibitor tincture of monoclonal antibody is necessary by inhibiting IL-6 binding to cells and soluble IL-6 And bl ock its classic and bypass IL-6 signal pathway, so after receiving the monoclonal antibody treatment, many patients quickly achieved a good clinical response [24]. CRS can be divided into 5 levels, different levels of recommended CRS treatment is different, it is generally recommended priority early adequate use of trastuzumab to prevent severe CRS response, but because IL-6 mAb is not easy through the blood-brain barrier, 3 to 4 neurotoxic patients, may be preferred to use glucocorticoids to prevent severe CRS. Therefore, IL-6 monoclonal antibody can be relatively early application, can be controlled for CRS and does not affect the efficacy of CAR-T 5. Summary and outlook Nowadays, the clinical application of CAR-T cell therapy, especially the treatment of CD19 CAR-T in hematologic tumors, has made great achievements and the application potential of adoptive immunotherapy as the main representative of CAR-T cell immunotherapy Is very broad. Not only in the blood disease, but also in solid tumors and many benign or chronic diseases, it also has a lot of potential applications. With the development of gene recombination technology and antigen protein construction technology, more CAR-T has been applied to precise targeted therapy. In addition, epitopes expressed on the surface of different blood tumor cells, such as: CD20, CD22, CD34, etc. may also be used as future treatment of other refractory blood diseases targeted to disease treatment to bring a new direction. One of the patients treated with CD19-modified CAR-T cells for MLL rearrangement of B-cell acute lymphoblastic leukemia showed that two patients developed AML after one month of treatment, wh ich may be related to the CD19-negative cellular immune escape Of a mechanism-related [25]. Therefore, the application of CAR-T in combination with multiple epitopes and the sustained killing effect of CAR-T cells in vivo may bring new hope to these cases. There have also been advances in the use of checkpoint inhibitors in combination with CAR-T in the treatment of animals such as AML [26]. However, CAR-T therapy is still a significant clinical risk of adverse treatment, therefore, CAR-T therapy to avoid the safety and toxicity is also a clinical problem to be solved. At present, CAR-T cell therapy for specific antigenic epitopes is combined with nonspecific traditional therapy for tumor cells. It is also a safe and reasonable regimen for the treatment of these diseases, not only killing the tumor cells completely, reducing immune escape and ineffective CAR-T cell immunotherapy, in turn, reduces the dose of non-targeted therapies such as prior chemotherapy and the consequent toxic reactions. Therefore, in the process of discovering new target antigens and constructing precise immunotherapy, The combination of non-targeted drugs and hematopoietic stem cell transplantation is also the research direction of CAR-T cell therapy for a long time. Thus, CAR-T cell therapy has provided new hope for refractory hematologic malignancies, and although there is a pleasing therapeutic effect, more research and further clinical trials are needed, Multi-angle, combined with previous and recent targeted therapy experience, will give CAR-T cell therapy to bring a broader application prospect and exciting clinical efficacy. 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[4] Jensen MC, Popplewell L, Cooper LJ, et al.Antitransgene rejection reponses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans[J].Biology of blood and marrow transplantation:journal of the American society for blood and Marrow transplantation, 2010, 16(9)à ¯Ã‚ ¼Ã… ¡1245-1256. [5] Kowolik CK, Topp MS, Gonzalez S, et al.CD28 Costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of aoptively tyansferred T cell[J].Cancer research, 2006, 66à ¯Ã‚ ¼Ã‹â€ 22à ¯Ã‚ ¼Ã¢â‚¬ °Ãƒ ¯Ã‚ ¼Ã… ¡10995-11004. [6] Sanchez-paulete AR, Labiano S, Rodriguez-ruiz ME, et al.Deciphering CD137(4-1BB) signaling in T cell costimulation for translation into successful cancer immunotherapy[J].European journal of immunology, 2016, 46(3):513-522. [7] Pule MA, Straathof KC, Dotti G, et al.A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of Primary human T cell[J].Molecular therapy:the journal of the American society of gene therapy, 2005, 12(5):933-941. [8] Zhao Y, Wang QJ, Yang S, et al.A herceptin-based chimeric antigen rcetor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity[J].Journal of immunology, 2009, 183(9):5563-5574. [9] Pegram HJ, Lee JC, Hayman EG, et al.Tumor-targeted T cells modified to secrete IL-12 cradicate systemic tumors without need for prior conditioning[J].Blood, 2012, 119(18):4133-4141. [10] Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing Eà ¯Ã‚ ¼Ã‚ ²BB2. Mol Ther, 2010; 18 ( 4) : 843-851à ¯Ã‚ ¼Ã… ½ [11] Jena B, Dotti G, Cooper L. à ¯Ã‚ ¼Ã‚ ²edirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood, 2010; 116 ( 7) : 1035-1044à ¯Ã‚ ¼Ã… ½ [12] Scholler J, Brady TL, Binder-scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cellsà ¯Ã‚ ¼Ã… ½ Sci Transl Medà ¯Ã‚ ¼Ã…’2012; 4( 132) : 132ra53à ¯Ã‚ ¼Ã… ½ [13] Brentjens RJ, Latouche JB, Santos E, et al.Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15.Nat Med, 2003; 9( 3) : 279-286. [14] Brentjens à ¯Ã‚ ¼Ã‚ ²J, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts.Clin Cancer à ¯Ã‚ ¼Ã‚ ²es, 2007; 13( 18) : 5426-5435. [15] Porter DL, Levine BL, Kalos M, et al.Chimeric antigen receptormodified T cells in chronic lymphoid leukemia.N Engl J Med, 2011; 365( 8) : 725-33à ¯Ã‚ ¼Ã… ½ [16] Kalos M, Levine BL, Porter, DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med, 2011; 3( 95):95 ra73. [18] Janka G.Familial and acquired hemophagocytic lymphohistiocytosis.Annu rev Med, 2012; 63( 1) : 233-246à ¯Ã‚ ¼Ã… ½ [19] Kohn DB, Dotti G, Brentjens R, et al. CARs on track in the clinic.Mol Ther, 2011; 19( 3) : 432-438à ¯Ã‚ ¼Ã… ½ [20] Maude SL , Barrett D, Teachey DT, et al. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies[J].Cancer journal(Sudbury, Mass), 2014, 20(2):119-122. [21] Grupp SA, kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia[J].The New England journal of medicine, 2013, 368(16):1509-1518. [22] Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells[J]Blood, 2012, 119(12):2709-2720. [23] Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome[J]Blood, 2014, 124(2):188-195 [24] Teachey DT, Rheingold SR, Maude SL, et al.Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy[J].Blood, 2013, 12(26):5154-5157 [25] Gardner R, Wu D, Cherian S, et al.Acquisition of a CD19-neg-ative myeloid phenotype allows immune escape of MLL-rear-ranged B-ALL from CD19 CAR-T-cell the rapy[J].Blood, 2016, 127(20):2406-2410. [26] Saad S Kenderian MR, OL ga Shestova, Michael Klichishky, et al.Idntification of PD1 and TIM3As Checkpoints that Limit Chimeric Anti gen Receptor T Cell Efficacy in Leukemia[j]Bood, 2015, 126(23):852-852

Reliability and Validity Matrix

TEST of Reliability | Application and APPROPRIATENESS| Strengths| Weaknesses| Internal Consistency| This measure of reliability is appropriate when trying to determine the difference in reliability from shortening or lengthening a test (Cohen & Swerdlik, 2010). Here I am specifically referring to the Spearman-Brown formula being used to determine internal consistency. A researcher could also use other measures of internal consistency meant for heterogeneous test items, such as Inter-item consistency. The reliability of a test increases with an increase in the number of test items. One of the strengths of the Spearman-Brown Formula is that is can determine how much more or less reliable a test is as a researcher lengthens or shortens the test. This measure can also work in reverse and tell a researcher how many items they need to add to reach a certain reliability coefficient. | The problem with the use of the Spearman-Brown formula to determine internal consistency is that it is only affective with homogenous test items, that is items that are the same difficulty and length.Also, tests of reliability are higher for whole-test vs. half-test applications of the formula, which means that lengthier tests work better with this instrument. | Split-half| The split-half form of measuring reliability entails creating two halves in the same test that can be compared in the same manner as the parallel form of reliability testing uses. This type of measurement is appropriate when using odd-even reliability or random assignment splits, but is most applicable when designing mini-parallel forms of the same test.In this instance, each half is, â€Å"†¦as nearly equal as humanly possible—in format, stylistic, statistical, and related aspects† (Cohen & Swerdlik, 2010, p. 145). | The strength of this kind of measure is that it is less time-consuming and less cumbersome for test-takers than the parallel form, but is also a good measure of internal consistency. T his type of measurement also help keep in check intermediary variables that might introduce error variance into the analysis, since the both parallel portions of the test are taken at once. However, there are several intermediary variables that are enhanced by this form of measuring reliability: fatigue that is felt during the second part of the test but not the first and variance in the difficulty or content of the items in the first half vs. the second half. It is also not advised to simply split a test down the middle. The different halves should have the same content and difficulty of question for the measure of reliability to be accurate. Test/retest| This type of test is applicable when the construct being measured is relatively stable over time, but is inappropriate for constructs that are not stable over time (Cohen & Swerdlik, 2010). This is because test/retest reliability is based on taking the same test, with the same people, at two different times. If the construct being measured is purported to change over time, then the scores of the test would vary because of true variance, rather than error variance—which is the basis of reliability, the latter that is. An example of this principle might be an achievement test measuring grammatical skills.If the test-taker undergoes a series of lessons on grammar between the first test and the second test, then the test will show variance, but not due to error but due to the intermediary variable of education. Test/retest reliability would be inappropriate in this situation. | The strength of this measurement of reliability are in tests that, â€Å"†¦employ outcome measures such as reaction time or perceptual judgment† (Cohen & Swerdlik, 2010, p. 143). This is because these types of psychometric traits do not vary greatly over time and are not sensitive to many types of intervening variable. The weakness of test/retest reliability is, of course, that the underlying constructs being tested can change over time, and therefore lower the test/retest reliability due to true variance rather than error variance. In this case, the overall reliability of a test might be seen as lower even though the actual measurement of the construct is stable (it is just that the construct itself varies). | Parallel and alternate forms| Both parallel and alternative forms of test reliability utilize multiple instances of the same test items at two different times with the same participants (Cohen & Swerdlik, 2010).These types of measures of reliability would be most appropriate with tests that measure traits that are stable over a long period of time and inappropriate when measuring finite emotional states or anxiety levels. | The strength of this measure of reliability is that it measures the core construct through several variances of the same test item. If equivalent scores are found on multiple forms of the same test item, then the reliability of the test will go up. Moreover, there are wa ys to perform this type of reliability analysis without having the test-taker undergo multiple examinations: internal onsistency estimate of reliability. This type of analysis would save time and money. | Designing these types of measures are time-consuming, expensive, and tiresome for the test-taker who has to take variations of the same test items over and over again. Also, these forms of testing reliability are not dependable for measuring constructs that change over time, such as anxiety levels. Another weakness is that if the tests are taken some time apart, then intervening variables might have an effect on the scores, thereby increasing error variance. Test of Validity| Application and APPROPRIATENESS| Strengths| Weaknesses| Face validity| Face validity is a description of the subjective perception of the test-taker of the test’s validity (Cohen & Swerdlik, 2010). This measure is not so much a quantification of the test’s actual validity, but a measure of the te st-taker’s perception of the test’s validity. Face validity is most appropriate when measuring the test-takers confidence that a test measures what it purports to measure. The strength of face validity is that if the test-taker has confidence in the validity of test, then they are more likely to take the test, and further the test user is more likely to administer the test. Without face validity, the test might be perfectly valid, but it is not administered or taken properly because the user/taker does not have confidence in the test. | The weakness of face validity is that it might not measure actual validity. A test can appear to be valid to the user/taker while also being completely invalid for the construct/time/place of the test.A good example might be the inkblot test. Psychologists that adhere to the psychodynamic perspective of psychopathology would say that the test is perfectly valid for determining personality characteristics, but the test taker might not un derstanding how the test applies to personality development, thereby undermining the face validity of the test. | Content validity| Measures of content validity are most useful in situations a test designer is trying to create test items that match the content of the material being tested (Cohen & Swerdlik, 2010).For instance, a final course exam should test the content area that the course covered. Further, this measure might not be applicable in situations where the skills that the test designer are looking for in the applicant are not currently part of the skill-set of the already employed, such as in cases of new positions. | One of the strengths of content validity is that it can used to work backwards from job responsibilities to job applicant requirements.First, the test designer would examine veteran workers perform their job, and then design an application process that looks for these qualities in a potential employee. The items that are judge essential for the job are the ones that are most advantageous for the applicant to possess. | The downfall of content validity is that the perspective of the material being covered is culturally and chronologically subjective, meaning that the questions can have different answers in different areas of the world or at different times.Therefore, the test items must be culturally and chronologically accurate for the test-takers for content validity to be used. | Criterion related| I know this is personal opinion, but I think that criterion-related validity is the most powerful of all of the methods of verifying validity—especially concurrent validity. This type of validity is used to verify that the criterion that the test score purports to represent is actually in the sample of individuals being tested (Cohen & Swerdlik, 2010).For instance, a group of people who have already been diagnosed with schizophrenia could be tested using a new instruments and if they all score high on the test for schizophrenia, th en the test can be said to have acceptable validity. | One of the strengths of criterion-related validity is that it is a very powerful measure of the actual validity of a test score. This type of validity uses methods external to the test itself to verify that the test covers the subject matter and criterion that it purports to cover. This fact alone makes this measure the most objective and verifiable of the measures of validity. A weakness of content validity is that criterion contaminations can occur, which is when the same predictor measure and criterion measure are used. As an example, if the diagnosis of a mental disorder by a panel of diagnosticians is used both as the test criterion and the measure of test validity. | Construct| Construct validity is the umbrella under which all of the other sub-types of validity fall (Cohen & Swerdlik, 2010). Construct validity is appropriate to use in cases where a test is trying to measure some underlying construct, such as intelligence or anxiety.I suppose this measure of validity might not be appropriate in situations where there is not one clear construct that is being measured, such as generalized achievement tests. | One of the main strengths of construct validity is that the procedures used to verify underlying constructs follow the edicts of the scientific method. A hypothesis is formulated, predicting that if someone possesses in great quantity the construct of intelligences—as verified through other measures—then they will score high on a test purporting to measure intelligence.In this way, a predictions is made based on scientific facts and then the test is used to determine if the prediction holds true. If it does not, then the test items, predictions, or underlying construct might need to be revised. | The downfall of this measure of validity is that if there is not one clear construct or if the construct is vaguely defined, then the validity of the test score is not measurable. So, the va lidity of the test rests on the underlying construct definition and specificity. |

The goal of the present paper is to discuss the different and shared properties

The goal of the present paper is to discuss the different and shared properties of photography and film with reference to the use of photographs in the film Paris qui dort (also known as Le rayon de la mort in France, and Paris asleep or The crazy ray internationally) by Renà © Clair (shot in 1923, the premier in France took place in 1925, in the United States – in 1926).Anne Friedberg once characterised this particular movie as â€Å"a narrative built around the shift from photography to film.†[1]   This quote indicates a channel for the discourse on the topic, how the French filmmaker synthesised photographic and cinematographic means to create a complex visual tissue.To remind the plot of this earlier example of cinematic science fiction, the main hero of the film called Albert (Henri Rollan), who is the watchman at the Eiffel Tower, awakens one perfect day to discover that the whole city of Paris has been fallen asleep. While he strolls down the streets of the bu siest European metropolis, the character observes people having been paralysed in their routine affairs. During his journey Albert meets five persons who have just arrived to Paris by airplane: Hesta (Madeleine Rodrigue), a self-made young traveller, a multi-millionaire who came to visit his bride (Antoine Stacquet), a hook and a police detective (Marcel Vallà ©e and Louis Prà © Fils), and a pilot (Albert Prà ©jean).These six occasional fellows in misery spend the night on the top of the Eiffel Tower and swoop into the city the next day to amuse themselves at their best.Having returned back to their shelter with precious loot, Albert and company catch the SOS-signal on the radio. In result of a purposeful search, the adventurers arrive at the cellar laboratory of Dr. Crase, a talented yet frenzied scientist (Charles Martinelli). Miss Crase, the professor's niece and assistant, meets the newcomers and tells them an interesting story.It appears that Dr. Crase has invented a wonderf ul machine that could arrest time by its rays. When the scientist tested his invention, all the six heroes enjoying the moment â€Å"happened to be, at three twenty-five, the moment of immobilization, at an altitude beyond its reach.†[2] Dr Crase was talented enough to design the formula for freezing the course of life but forgot to devise an antidote. Upon persuasion, he corrects his mistake, and Paris is permitted to return back to the usual mode of life.The members of the warm company separate from each other. Albert finds himself accompanying Miss Crase. The young man likes the girl and decides to see her back to her place but finds no cash to pay for the cab. He decides to immobilise the city one more time to stock up on money for the rest of his life. Albert rushes to Dr. Crase’s laboratory and struggles with the professor over the machine’s levy. Depending on their movements, the life in Paris is either set still or resumed in mobility. The battle ends up with an explosion.The heroes of the movie try to explain to the police what has happened. Nobody believes them so far as the rest of the Parisians, who have fallen asleep, do not remember the period of immobilisation. Finally, Albert is almost persuaded that Dr. Crase and his invention have been just his nightmares. However, upon return to the Eiffel Tower hand-in-hand with Miss Crase, the hero finds a diamond ring in the aperture between the girders. It was one of the trophies that the merry gang brought from the journey across the frozen city. The ring makes Albert believe once again in the existence of immobilising rays.[3]Before deciphering Friedberg’s idea about Clair having synthesised the performative possibilities of photography and cinematography, and before sharing some original ideas, the author feels obliged to analyse the technical and cultural backgrounds of these two interrelated media.Researchers started investigating the semiotic value of photography as the precedent to cinematography as early as in the mid-19th century. At the dawn of invention, photography was perceived as a technique to make light â€Å"exert an action †¦ sufficient to cause changes in material bodies.†[4] The idea was expressed by Fox Talbot in a book The pencil of nature, published in 1844. Rosalind Krauss chose the treatise as a field for analysis to discuss a dynamics of symbolic complexity associated with photography throughout its development. Her discourse is especially interesting so far as it explores the earlier metaphysical values ascribed to photography in the 1840s and the most recent semiological explanations of this art.To summarise the section of Krauss’ article dealing with the earlier representations of photography, the latter was perceived as a complex phenomenon existing both at the physical and metaphysical layers. On the one hand, it was often compared to â€Å"the footprint that is left on sand.†[5]To put it different ly, a well-known light spectrum was refracted inside a photographic camera so that the representations of people and other animate and inanimate objects were imprinted on the plates and photographic paper. On the other hand, Talbot and his contemporaries were intrigued by â€Å"certain invisible rays† which let â€Å"the eye of the camera †¦ see plainly where the human eye would find nothing but darkness.†[6][1] A. Friedberg, Window shopping: cinema and the postmodern, Berkeley and Los Angeles, CA, USA, University of California Press, 1993, p. 102. [2] Miss Crase’s words, cited in A. Michelson, Dr. Crase and Mr. Clair, October, 11: Winter, 1979: p. 34. [3] A detailed summary of the movie plot is provided by Michelson, pp. 33-34. [4] W. Fox Talbot, The pencil of nature, facsimile edition, New York, Da Capo Press, 1969, introduction, n.p., cited in R. Krauss, Tracing Nadar, Photography, 5: Oct. 1978: p. 39. [5] Krauss, Tracing Nadar, p. 33. [6] Talbot, cited in Krauss, Tracing Nadar, p. 41.

Viscosity Lab Essay - 721 Words

Viscosity Science Lab Purpose: To determine of changing the viscosity will affect the time it takes for a marble to flow through a liquid. Hypothesis: If a marble is dropped into dish soap and corn syrup, than I predict that the marble in the dish soap will travel faster than the marble in the corn syrup because I know that the viscosity of the corn syrup is thicker than then the viscosity of the dish soap. Also, the particles in the corn syrup are more compact than those in the dish soap. This makes the marble sink faster in the dish soap than the corn syrup. Apparatus: * 2 identical marbles * 250 Graduated Cylinders of 250mL * 250mL of dish soap * 250mL of corn syrup * 1 timer/stopwatch Procedure: 1.†¦show more content†¦It is very difficult for large particles to move past each other unlike small, tiny particles, like those in the dish soap. The particles in the dish soap are very small and can move more freely and quickly. In the dish soap, the particles are very small and can move past each other easily when compared to the particles in the corn syrup. Another reason also contributed to the result of this experiment. Attraction. Some types of particles tend to attract more than others and that is exactly what happened in the corn syrup. The particles in the corn syrup attracted more than the dish soap. The large particles in the corn syrup held tightly to each other, that when the marble fell in that it made it hard for the marble to pass through more than one particle at a time. IN the dish soap, the particles did not attract as much as the corn syrup which let the marble move easily and quickly through the liquid. The strength of attraction as well as the particle size is important in determining a fluid’s viscosity. Application: This viscosity experiment can be used in real-life when making sun-tan lotion as well as other cosmetic products. It is important for the lotion to be viscous because the lotion could not be applied and spread around the body if the cream was not viscous enough to suit its use. It would drip all over you! It wouldn’t dry or stay in one place. Many well-known businesses hire highly educated scientists to calculate the right viscosity level and if it isShow MoreRelatedLab Report On Viscosity : Newtonian Vs. Non Newtonian Fluids1722 Words   |  7 Pages Laboratory Report 3 Viscosity: Newtonian vs. Non-Newtonian Fluids By Jennifer Blanchard Olivia George Todd Lynn Chantz Yanagida ENGR 3070L CRN: 47426 27 September 2017 Jacqueline H. 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