Biomarkers of Age-Related Frailty and Frailty Related to Diseases: An Exploratory, Cross-Sectional Analysis from the MAPT Study.

BACKGROUND: Frailty may in most cases result from two main causes: the aging process (age-related frailty) and diseases (evolving chronic conditions or acute medical illnesses - disease-related frailty). The biological determinants characterizing these two main causes of frailty may be different. OBJECTIVES: The aim of this study is to compare the biological and neuroimaging profile of people without frailty, those with age-related frailty, and subjects with disease-related frailty in community-dwelling older adults. MATERIAL AND METHODS: We performed a secondary, cross-sectional analysis from the Multidomain Alzheimer Preventive Trial (MAPT). We included 1199 subjects without frailty throughout the 5-year follow-up, 82 subjects with incident age-related frailty, and 53 with incident disease-related frailty. Available blood biomarkers involved nutritional (eg, vitamin D, omega-3 fatty acids), inflammatory-related (IL-6, TNFR1, GDF15), neurodegenerative (eg, beta-amyloid, neurofilament light chain) and neuroimaging markers (MRI, Amyloid-PET). RESULTS: Although not statistically significant, the results of the unadjusted model showed increasing gradients for inflammatory markers (GDF15, TNFR1) and decreasing gradients for nutritional and neuroimaging markers (omega 3 index, hippocampal volume) from age-related frailty participants to individuals with disease-related frailty. Considering the linear models we observed higher GDF15 values in disease-related frailty group compared to age-related frailty individuals [ß = 242.8 (49.5, 436.2)]. We did not find any significant difference between subjects without frailty and those with age-related frailty. Subjects with disease-related frailty compared to subjects without frailty had lower values of DHA [ß = -2.42 (-4.76, -0.08)], Omega 3 Index [ß = -0.50 (-0.95, -0.06)] and hippocampal volume [ß = -0.22 (-0.42,-0.02)]. They also had higher values of GDF15 [ß = 246.1 (88.9, 403.4)] and TNFR1 [ß = 157.5 (7.8, 307.2)]. CONCLUSION: Age-related frailty and disease-related frailty may represent different degrees of frailty severity on a biological level. Further research is needed to identify biomarkers potentially able to distinguish these classifications of frailty.

The INSPIRE Bio-Resource Research Platform for Healthy Aging and Geroscience: Focus on the Human Translational Research Cohort (The INSPIRE-T Cohort).

BACKGROUND: The Geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (IC) (body functions) leading to dependency. A better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. OBJECTIVES: The main objective of the INStitute for Prevention healthy agIng and medicine Rejuvenative (INSPIRE) Platform initiative is to build a program for Geroscience and healthy aging research going from animal models to humans and the health care system. The specific aim of the INSPIRE human translational cohort (INSPIRE-T cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. METHODS: The INSPIRE-T cohort consists in a population study comprising 1000 individuals in Toulouse and surrounding areas (France) of different ages (20 years or over - no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. Diversified data are collected annually in research facilities or at home according to standardized procedures. Between two annual visits, IC domains are monitored every 4-month by using the ICOPE Monitor app developed in collaboration with WHO. Once IC decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time IC declines are detected. Biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. Nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. Feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. EXPECTED RESULTS: Recruitment started on October 2019 and is expected to last for two years. Bio-resources collected and explored in the INSPIRE-T cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and IC evolution that could be pharmacologically or non-pharmacologically targetable. The INSPIRE-T will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging.

Attitudes of the public and scientists to biotechnology in Japan at the start of 2000.

This survey on biotechnology and bioethics was carried out on national random samples of the public and scientists in November 2000-January 2000 [sic]throughout Japan, and attendees at the Novartis Life Science Forum held on 29 September 1999 in Tokyo. The sample size was 297, 370, and 74 respectively. While there is a better awareness of GMOs in 2000 compared to 1991; the trend shows an increase in the perceived risks of GMOs followed by growing resistance in Japan. While a majority of persons believed genetic engineering would make life better over the next twenty years (57%), the proportion of respondents who thought genetic engineering would make life worse over the next twenty years doubled from 1997 to 2000 (from 12% to 25%). Respondents were asked whether they had heard about applications in several areas and the order of familiarity (high-low) was: pest-resistant crops, human genes in bacteria, mouse to develop cancer, food and drinks, pigs with human hearts and pre-implantation diagnosis. A divide of opinion can be seen when the results on benefit, risk and moral acceptability of applications of biotechnology by the public are compared to the forum and scientist samples. A significant change in the acceptance of the public occurred in 2000 where only 22% agreed on the moral acceptability of GM food compared to 41% in 1997. In 2000 fewer people said they are willing (20%) to buy genetically modified fruits that taste better compared to 1997 (36%). The results show less public support for use of gene therapy than 1993 and twice as many scientists rejected gene therapy than they did in 1991. When asked who is best placed to regulate modern biotechnology, the respondents were overwhelmingly in favor of international regulatory bodies, such as the United Nations and the World Health Organization (72%), rather than national bodies. The comparison between scientists and public is interesting, however the more enthusiastic sample were participants from the Novaritis Life Science Forum with its mixed occupations.

[A phase II study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with head and neck cancer].

A phase II study of a new anthracycline, (2"R)-4'-O-tetrahydropyranyladriamycin (THP), was conducted in 110 patients with various head and neck cancers in a multi-institutional cooperative study. The response rate was 20.3% (PR 12) in an intravenously injected group and 52.3% (CR 8, PR 15) in an intraarterially injected group. In the former cases, the response rate according to primary sites was 19.2 to 27.3% for the maxilla, pharynx, oral cavity and larynx. In the latter cases, it was 40.9 to 64.3% for the maxilla, pharynx and oral cavity, and 100% for the external auditory meatus (CR 1, PR 1). According to histology, the response rate was 37.5 % in squamous cell carcinoma. Partial response was observed in two cases of undifferentiated carcinoma. The predominant toxicity was myelosuppression. Leukocytopenia (less than 3,000/mm3) was noted in 44 cases (41.9%). Loss of hair and stomatitis were observed in 13 (12.6%) and 12 (11.7%) respectively. However, these were mild and recovered quickly on discontinuation of THP. We concluded that THP therapy was markedly effective for various head and neck cancers.

[Phase II study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with solid tumors. Multi-Institutional Cooperative Study].

A Phase II Study of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with various solid tumors was carried out by 44 cooperative study institutions. Seven hundred fifty-six patients administered the drug intravenously were entered into this study. Of these, 499 patients were evaluated for objective responses. THP was given mainly at a dose of 40 to 60 mg/body every 3 to 4 weeks or 20 to 30 mg/body once a week. Response rates were 18.8% for head and neck cancer, 13.1% for stomach cancer, 21.4% for breast cancer, 22.2% for bladder cancer, 30% for renal pelvic and urinary tract tumor, 26.8% for ovarian cancer and 24.2% for uterine cancer. Overall response rate was 15.4% including 10 complete responses and 67 partial responses. Adverse reactions were similar to those previously reported in the phase I study, including gastrointestinal toxicities and myelosuppression. Alopecia and stomatitis, which are major side effects of other anthracyclines, were rather mild. Incidence of ECG changes was 2.8% and no congestive heart failure was observed.

[A cooperative phase II study of cisplatin in patients with head and neck cancer].

A cooperative phase II study of cisplatin in head and neck cancer was conducted in 23 institutions. Eighty-nine patients were entered into this trial, of which 73 were evaluable. Two different regimens were employed in this study. Regimen A: cisplatin 10 mg/m2 intravenous (i.v.) infusion daily, days 1-5, q 3 wk. Regimen B: cisplatin 50 mg/m2 i.v. infusion, day 1, q 3 wk. Two patients achieved complete response and 17 achieved partial response with an overall response rate of 26.0%. By histological types, the response rate was 26.3% in the case of squamous cell carcinoma. Partial response were observed in 2 cases of adenocarcinoma and in one case each of adenoid cystic carcinoma and transitional cell carcinoma. The response rate was 19.4% for previously treated patients, as compared to 63.6% for the previously untreated group. Toxic effects were observed in 94.7% of 76 evaluable cases. From 50 to 68% of patients experienced nausea, vomiting and anorexia. No patient exhibited a serum creatinine level exceeding 2 mg/dl. Anemia and leukopenia were observed in 58.9% and 32.9% respectively. It is therefore concluded that cisplatin is markedly useful for the treatment of head and neck cancer.

[Phase II study of UFT for head and neck cancer].

A Phase II study of UFT for head and neck cancer was conducted in 10 institutions. UFT is a mixture of Futraful and uracil. Eighty-four patients entered this trial, of which 60 were evaluable. UFT was administered orally at a daily dose of 600 mg/day. Eight patients achieved complete response and 10 achieved partial response with an over-all response rate of 30.0 %. Evaluating response according to by histology, the response rate was 30.9% for cases of squamous cell carcinoma. Complete response was observed in one case of undifferentiated carcinoma. Response rate according to primary site was 33 to 40% for the nose & paranasal sinuses, mesopharynx, hypopharynx and larynx. The response rate was 28.9% for the group of patients treated previously, and 33.3% for the group previously untreated. The mean time for 50% or more regression of the tumor was 4.3 weeks. Toxic effects appeared in 40.3% of 67 evaluable cases as anorexia, nausea, vomiting, stomatitis, diarrhea etc. In one case of maxillary carcinoma, severe bone marrow suppression was observed. We concluded that UFT therapy was markedly effective for head and neck cancer.

Intraarterial infusion of 4'-O-tetrahydropyranyl-adriamycin for head and neck tumors.

THP-adriamycin was administered in a dose of 5 to 20 mg, 3 times a week, and the results showed 4 cases of CR, 5 cases of PR, 3 cases of MR and 2 cases of NC with the accumulated total dose of less than 100 mg. Histological effects were slight in a total dose of less than 50 mg, while the effects appeared in a total dose of 60 to 70 mg and further effects were obtained after about 1 week of the termination of the therapy. Leukopenia occurred in 6 of 14 cases. The side effects of THP-adriamycin were milder than those of ADM.

[THP-adriamycin in head and neck tumor].

Primary effects and side-effects of a new anthracycline antineoplastic agent, THP-adriamycin (THP-ADM), were examined in 20 patients with malignant head and neck tumors. According to a classification by tumor sites, there were 6 cases of oropharynx, 6 of nose and sinuses, 3 of tongue, 2 of floor of mouth, 2 of neck and 1 of external auditory meatus. According to the tissue classification, there were 11 cases of squamous cell ca., 6 cases of malignant lymphoma, each one case of anaplastic ca., carcino sarcoma and adeno cystic ca. There were 16 previously untreated cases and 4 pretreated cases. Twelve cases received THP-ADM by intraarterial injection and 8 cases by the same dose. 10 to 20 mg/body 3 times a week, in a total of 40 to 100 mg. 2 CR, 5 PR, 3 MR and 4 NC in 14 cases with carcinoma, and 2 CR, 3 PR and 1 MR in 6 cases with malignant lymphoma were obtained. Among 12 cases receiving intraarterial injection, 3 CR and 5 PR were obtained. The decrease of WBC counts below 3000/mm3 after THP-ADM administration was observed in 9 cases. Side effect of THP-ADM appeared to be less severe than that of Adriamycin.

[Clinical results of FAR (5-FU, vitamin A, and radiation) therapy in head and neck cancer].

Combination therapy of 5-FU, vitamin A and radiation (FAR therapy) was given to 50 patients with squamous cell carcinoma of the head and neck. The primary effect was observed in 22 patients who received FAR therapy as radical therapy. Among them, only 4 patients had recurrence or metastasis, and death was none. FAR therapy was given to 4 patients as pre-operative therapy and to 2 patients as post-operative therapy. However, the number of cases was not enough for us to draw any conclusion. In the group of 22 patients consisting of patients with recurrence or metastasis and patients who refused operation or were unresectable, no primary effect was observed only in 4 patients. Among a total of 50 patients, only 4 patients did not show a primary response to FAR therapy, 19 had relapse, 19 died (6 cases of them died from other causes), and 31 are still alive. There were no patients having severe side effects. From these results, FAR therapy seemed to be worth trying in treatment of head and neck cancer.