Two different point mutations in ABL gene ATP-binding domain conferring Primary Imatinib resistance in a Chronic Myeloid Leukemia (CML) patient: A case report

Imatinib (Gleevec) is the effective therapy for BCR-ABL positive CML patients. Point mutations have been detected in ATP-binding domain of ABL gene which disturbs the binding of Gleevec to this target leading to resistance. Detection of mutations is helpful in clinical management of imatinib resistance. We established a very sensitive (ASO) PCR to detect mutations in an imatinib-resistant CML patient. Mutations C944T and T1052C were detected which cause complete partial imatinib resistance, respectively. This is the first report of multiple point mutations conferring primary imatinib resistance in same patient at the same time. Understanding the biological reasons of primary imatinib resistance is one of the emerging issues of pharmacogenomics and will be helpful in understanding primary resistance of molecularly-targeted cancer therapies. It will also be of great utilization in clinical management of imatinib resistance. Moreover, this ASO-PCR assay is very effective in detecting mutations related to imatinib resistance

Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia

Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.Peer reviewe

Seasonal variation of non-shivering thermogenesis (NST) during mild cold exposure

Background: The physiological function of non-shivering thermogenesis (NST) has been investigated in recent years, and some studies have discussed the importance of NST with respect to human cold adaptation. The present study aimed to clarify individual and seasonal variations in NST that occurred as a result of mild cold exposure.Methods: Seventeen male university students participated in the present study during summer and winter. The climate chamber used was programmed so that ambient temperature dropped from 28°C to 16°C over an 80-min period. Physiological parameters of test subjects were recorded during the experiments.Results: Increases in oxygen intake (VO2) during cold exposure were significantly greater without shivering in winter than they were in summer. Respiratory exchange ratio (RER) was significantly lower during thermoneutral baseline and cold exposure in winter than it was during the same periods in summer. In addition, there was a significant negative correlation between ΔVO2 and ΔRER.Conclusions: Increase of VO2 without shivering indicated increase of NST, and decrease of RER depends on the metabolization of fat in winter. These results suggested that NST activity was activated by seasonal acclimatization, and individual variation of NST depends on individual variation of fat metabolism

European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia

Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.Peer reviewe

Relationship between mitochondrial haplogroup and seasonal changes of physiological responses to cold

Background: Physiological responses to cold exhibit individual variation that can be affected by various factors, such as morphological characteristics, seasonal changes, and lifestyle; however, the genetic factors associated with this variation remain unclear. Recent studies have identified mtDNA as a potential genetic factor affecting cold adaptation. In addition, non-shivering thermogenesis (NST), a process closely related to mitochondrial dynamics, has also been suggested as an important factor affecting human response to cold. The present study aimed to clarify the relationship between mitochondrial haplogroup and NST during periods of mild cold exposure.Methods: Seventeen healthy university students (D: n = 8, non-D: n = 9) participated in the present study during summer and winter. A climate chamber was programmed so that ambient temperature inside dropped from 28°C to 16°C over the course of an 80-minute period. Physiological parameters were recorded throughout the course of the experiments.Results: Increases in VO2 were significantly greater during periods of cold exposure in winter than they were during periods of cold exposure in summer, and individuals from the D group exhibited greater winter values of ΔVO2 than individuals from the non-D group.Tre was significantly lower during periods of rest and cold exposure in winter; however, no significant difference was observed between Tre values of individuals in the D and non-D groups. In addition, although T-dist was significantly lower during periods of rest in winter than it was during those same periods in summer, no significant seasonal differences in values of T-dist were observed during periods of cold exposure.Conclusions: Results of the present study indicated that NST was greater in winter, and that the D group exhibited greater NST than the non-D group during winter. Despite the differences between groups in NST, no significant differences in rectal and skin temperatures were found between groups in either season. Therefore, it was supposed that mitochondrial DNA haplogroups had a greater effect on variation in energy expenditure involving NST than they had on insulative responses. Future studies are necessary in order to investigate more multiple candidate genes related to human cold adaptation and to elucidate the relationship between gene polymorphism and physiological polytypism

Ethnic and Anthropometric Factors in Finger Cooling: Japanese and Europeans of Hawaii

Using moving 0°C air, a finger and moderate total body cooling exposure (70 minutes) was completed on 33 Japanese and 24 European young men. Interference by differential acclimatization was eliminated by use of subjects raised and now living in the tropics. Europeans showed a 16.7 percent frequency of inadequate finger temperature response, compared to only 3.0 percent in the Oriental sample. The difference was not significant statistically. In both groups, cooled finger temperature showed a modest but clear positive correlation to relatively long-trunked body build, and to finger temperature before cooling (during control period). The Japanese showed additional positive correlations between finger warmth and both body skinfolds and head size. Although the Europeans had higher CIVD amplitudes, the overall pattern of vasoactivity, comparing the groups, was similar. The Japanese sample was of sufficient size to run an internal analysis of CIVD. Those with two or more CIVD’s clearly enjoyed higher finger temperatures; they likewise showed higher core temperature and pulse rate. No CIVD to anthropometric associations were found with the possible exception of abdominal skinfold

Finger Temperatures During Work in Natural Cold: The Northern Ojibwa

Finger temperatures were collected from six groups of cold-acclimatized Northern Ojibwa Indian men as they worked outdoors during January and February in their subarctic ecozone. Variables which influenced thermal levels were exercise, insulation of hands, use and non-use of hands, am­bient temperatures, and windchill. Even with the high windchill (1350) the men, regulating their own pace and clothing, maintained very warm, comfortable, dexterous hands without difficulty. Three field experiments in which exercise and insulation of hands were manipulated and three others during which the men performed their normal tasks were compared. Both lack of continuous exercise and handling cold materials reduced hand temperatures considerably, and removal of mittens induced even greater losses as expected. However, the amount of variation seen in these responses suggests that some individuals may have to compensate for hand cooling more vigorously than others. Behavioral responses to this challenge are outlined

Hand Immersion in Cold Water at 5°C in Sub-Arctic Algonkian Indian Males from Two Villages: A European Admixture Effect?

Data from adult men in two Algonkian Indian villages in the Eastern Subartic (Northern Ontario) are presented for anthropometric measurements and for thermal response to a cold-induced vasodilation test involving hand immersion in 5°C water. Historical evidence and results from studies of genetic admixture suggest that the population of the villages differ significantly in the frequency of “Caucasian” genes.It is argued that differences in thermal response to cold-water exposure are related to the different amounts of genetic admixture which each village has experienced, rather than to the effects of small sample size, clinal distributions of thermal re­sponses, or other variables