Ligand-induced autoregulation of IL-2 receptor {alpha} chain expression in murine T cell lines

The IL-2 receptor (IL-2R) is composed of three chains a, ßand . In mice, contrary to the human system, we have previouslydemonstrated that the IL-2Rß complex does not bindIL-2. Therefore, mouse IL-2 response is completely dependenton the expression of the IL-2R gene product. T cell clones expressingmouse IL-2Rß and the human IL-2R transgene have beenstudied. When cells are grown in IL-4, mouse IL-2R is not expressed.However, exposure to IL-2 leads to the expression of the endogenousmurine IL-2R subunit. The T cell line expressing mouse IL-2Rand human IL-2Rß can grow in IL-2 but does not expressendogenous murine IL-2 R. Transfection of these cells with thehuman IL-2R gene restores the capacity to induce murine IL-2R.This result demonstrates that IL-2-IL-2R interactions are requiredfor induction of IL-2R. The kinetics of induction and deinductionof murine IL-2R have been studied using clone 18.III. From negativecells, expression of murine IL-2R is a very slow phenomenon.From cells fully expressing IL-2R, deinduction is a two-stepprocess: after a rapid decrease of IL-2R the cells continueto express, for a long period of time, basal levels of murineIL-2R. When cells expressing basal levels of IL-2R are exposedto IL-2, induction of IL-2R is a very rapid phenomenon. Theautoregulatory loop formed by IL-2-IL-2R therefore displaysdifferent levels of functioning.     

Vaccine-induced binding and neutralizing antibodies against Omicron 6 months after a homologous BNT162b2 booster

Evidence about the long-term persistence of the booster-mediated immunity against Omicron is mandatory for pandemic management and deployment of vaccination strategies. A total of 155 healthcare professionals (104 COVID-19 naive and 51 with a history of SARS-CoV-2 infection) received a homologous BNT162b2 booster. Binding antibodies against the spike protein and neutralizing antibodies against Omicron were measured at several time points before and up to 6 months after the booster. Geometric mean titers of measured antibodies were correlated to vaccine efficacy (VE) against symptomatic disease. Compared to the highest response, a significant 10.2- and 11.5-fold decrease in neutralizing titers was observed after 6 months in participants with and without history of SARS-CoV-2 infection. A corresponding 2.5- and 2.9-fold decrease in binding antibodies was observed. The estimated T_1/2 of neutralizing antibodies in participants with and without history of SARS-CoV-2 infection was 42 (95% confidence interval [CI]: 25–137) and 36 days (95% CI: 25–65). Estimated T_1/2 were longer for binding antibodies: 168 (95% CI: 116–303) and 139 days (95% CI: 113–180), respectively. Both binding and neutralizing antibodies were strongly correlated to VE (r = 0.83 and 0.89). However, binding and neutralizing antibodies were modestly correlated, and a high proportion of subjects (36.7%) with high binding antibody titers (i.e., >8434 BAU/ml) did not have neutralizing activity. A considerable decay of the humoral response was observed 6 months after the booster, and was strongly correlated with VE. Our study also shows that commercial assays available in clinical laboratories might require adaptation to better predict neutralization in the Omicron era.     

Testicular degeneration in three patients with the persistent müllerian duct syndrome

The presistent Müllerian duct syndrome, characterized by the presence of uterus and tubes in males, is a familial disorder due to defects of synthesis or action of anti-Müllerian hormone, a Sertoli cell glycoprotein responsible for the regression of Müllerian derivatives in normal male fetuses. Patients are normally virilized and testicular production of testosterone is normal. Both testes my be cryptorchild; alternatively, one may be descended into the inguinal canal or scrotum, together with the Müllerian derivatives, a condition known as hernia uteri inguinalis. We have recently observed three patients affected by the presistent Müllerian duct syndrome who experienced progressive degeneration of testicular tissue. In two, functional testicular tissue was still present some months after birth, but deteriortated progressively later. In one patient, testicular tissue was already absent at birth, but the normal virilization of external genitalia indicated that testicular degeneration must have occurred lat during fetal life, after the expected time of regression of male Müllerian ducts.Conclusion The high incidence of degeneration of testicular tissue in the presistent Müllerian duct syndrome could be indirectly linked to anatomical abnormalities which could favour testicular torsion, known to induce testicular regression.     

Assessment of physical activity and sleep by actigraphy: examination of gender differences

Research evidence suggests that actigraphy is a very important instrument in documenting sleep/wake patterns of people with a variety of sleep disorders or motor dysfunctions. The present actigraphic investigation examined physical activity and sleep profiles as a function of gender in volunteers monitored in their natural environment. Irrespective of age, women exhibited better sleep quality than did men. This was demonstrated by higher sleep efficiency index and lower frequency of transitions between sleep and wakefulness. Additionally, women slept more than men and had shorter sleep onset latency. However, no significant gender effect on daytime activity level and circadian activity amplitude was observed.     

Non-familial Creutzfeldt-Jakob disease: a study of 53 cases

Creutzfeldt-Jakob disease (CJD) is the most frequent human spongiform encephalopathy. We have analyzed 53 cases of definite non familial CJD over a study period of 28 years. All were autopsied in the same neuropathological unit. Clinical and epidemiological data were in accordance with previous studies: low incidence of CJD under the age of 40, high incidence around the sixty years of age (26%) a sex ratio at 0.65 and high frequency of myoclonus, dementia and cerebellar ataxia during evolution (78%). This study highlights the rapidity at the onset of the disease (within 24 hours) in 16% of the cases. EEG disclosed typical pseudoperiodic activity in only 53% of cases and cerebral MRI showed high T2 signal intensity in basal nuclei in 15%. This regional study is the second of its nature to be carried out in France, the first one covering the area of Paris.     

Characterization and multiparameter analysis of visual adverse events in irofulven single-agent phase I and II trials.

PURPOSE: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines. EXPERIMENTAL DESIGN: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis. RESULTS: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses < or =0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of < or =0.50 mg/kg and < or =20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. CONCLUSIONS: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of < or =0.50 mg/kg or < or =20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.     

Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis.

PURPOSE: Radiation-induced fibrosis (RIF) is a rare morbid complication of radiotherapy, without an established method of management. RIF treatment with a combination of pentoxifylline (PTX) and alpha-tocopherol (vitamin E; Vit E) was recently prompted by the good results of a clinical trial and an animal study. The present double-blind, placebo-controlled, monocentric study was designed to assess the efficacy of this combination in treating RIF sequelae. PATIENTS AND METHODS: Twenty-four eligible women with 29 RIF areas involving the skin and underlying tissues were enrolled from December 1998 to April 2000. These patients, previously irradiated for breast cancer, were randomly assigned to four balanced treatment groups: (A) 800 mg/d of PTX and 1,000 U/d of Vit E; (B) PTX plus placebo; (C) placebo plus Vit E; and (D) placebo-placebo. The main end point measure was the relative regression of measurable RIF surface after 6 months of treatment. Assessment was completed by depth (with ultrasonography) and associated symptom measures. RESULTS: Twenty-two patients with 27 RIF areas were analyzed at 6 months. Mean RIF surface regression was significant with combined PTX/Vit E versus double placebo (60% +/- 10% v 43% +/- 17%; P =.038). The median slope for the speed of RIF surface area and volume regression was significantly higher for group A than groups B, C, and D. All treatments were well tolerated. CONCLUSION: Six months' treatment of combined PTX/Vit E can significantly reduce superficial RIF. Synergism between PTX and Vit E is likely, as treatment with each drug alone is ineffective, but these results require confirmation in larger series.     

How to optimize physicians' communication skills in cancer care: results of a randomized study assessing the usefulness of posttraining consolidation workshops.

PURPOSE: Although there is wide recognition of the usefulness of improving physicians' communication skills, no studies have yet assessed the efficacy of post-training consolidation workshops. This study aims to assess the efficacy of six 3-hour consolidation workshops conducted after a 2.5-day basic training program. METHODS: Physicians, after attending the basic training program, were randomly assigned to consolidation workshops or to a waiting list. Training efficacy was assessed through simulated and actual patient interviews that were audiotaped at baseline and after consolidation workshops for the consolidation-workshop group, and approximately 5 months after the end of basic training for the waiting-list group. Communication skills were assessed according to the Cancer Research Campaign Workshop Evaluation Manual. Patients' perceptions of communication skills improvement were assessed using a 14-item questionnaire. RESULTS: Sixty-three physicians completed the training program. Communication skills improved significantly more in the consolidation-workshop group compared with the waiting-list group. In simulated interviews, group-by-time repeated measures analysis of variance showed a significant increase in open and open directive questions (P =.014) and utterances alerting patients to reality (P =.049), as well as a significant decrease in premature reassurance (P =.042). In actual patient interviews, results revealed a significant increase in acknowledgements (P =.022) and empathic statements (P =.009), in educated guesses (P =.041), and in negotiations (P =.008). Patients interacting with physicians who benefited from consolidation workshops reported higher scores concerning their physicians' understanding of their disease (P =.004). CONCLUSION: Consolidation workshops further improve a communication skills training program's efficacy and facilitate the transfer of acquired skills to clinical practice.     

Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). PATIENTS AND METHODS: Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. RESULTS: Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. CONCLUSION: The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.