Imaging rotational energy transfer: comparative stereodynamics in CO + N2 and CO + CO inelastic scattering.

State-to-state rotational energy transfer in collisions of ground ro-vibrational state 13CO molecules with N2 molecules has been studied using the crossed molecular beam method under kinematically equivalent conditions used for 13CO + CO rotationally inelastic scattering described in a previously published report (Sun et al., Science, 2020, 369, 307-309). The collisionally excited 13CO molecule products are detected by the same (1 + 1' + 1'') VUV (Vacuum Ultra-Violet) resonance enhanced multiphoton ionization scheme coupled with velocity map ion imaging. We present differential cross sections and scattering angle resolved rotational angular momentum alignment moments extracted from experimentally measured 13CO + N2 scattering images and compare them with theoretical predictions from quasi-classical trajectories (QCT) on a newly calculated 13CO-N2 potential energy surface (PES). Good agreement between experiment and theory is found, which confirms the accuracy of the 13CO-N2 potential energy surface for the 1460 cm-1 collision energy studied by experiment. Experimental results for 13CO + N2 are compared with those for 13CO + CO collisions. The angle-resolved product rotational angular momentum alignment moments for the two scattering systems are very similar, which indicates that the collision induced alignment dynamics observed for both systems are dominated by a hard-shell nature. However, compared to the 13CO + CO measurements, the primary rainbow maximum in the DCSs for 13CO + N2 is peaked consistently at more backward scattering angles and the secondary maximum becomes much less obvious, implying that the 13CO-N2 PES is less anisotropic. In addition, a forward scattering component with high rotational excitation seen for 13CO + CO does not appear for 13CO-N2 in the experiment and is not predicted by QCT theory. Some of these differences in collision dynamics behaviour can be predicted by a comparison between the properties of the PESs for the two systems. More specific behaviour is also predicted from analysis of the dependence on the relative collision geometry of 13CO + N2 trajectories compared to 13CO + CO trajectories, which shows the special 'do-si-do' pathway invoked for 13CO + CO is not effective for 13CO + N2 collisions.

Detection of the O2 A'3ΔU Herzberg III state by photofragment imaging.

Photofragment imaging is shown to provide a sensitive method for detection of the O2 A'3Δu Herzberg III state using a one-laser dissociation/O(1D) resonance enhanced multiphoton ionization (REMPI) scheme with a focused nanosecond dye laser beam tuned to 203.8 or 205.2 nm, combined with velocity map imaging of the atomic oxygen photofragment. O2 populated in the Herzberg states is generated by photodesorption at 250 nm of solid O2 ice held at 15 K and by an electric discharge in a pulsed molecular beam of pure O2. Ice photo-desorption results in Herzberg state products with higher translational, vibrational and rotational energy spreads, yielding the same signal as the discharge source but with lower velocity resolution. A clear signal with parallel character (ß âˆ¼ 0.9) assigned to dissociation of O2 A'3Δu(v = 0, 1 Ω = 1) was observed when using a pulsed electric discharge source under specific 'cold' conditions with O(1D) detection, driving one-photon dissociation around 205 nm. No products corresponding to O2 A'3Δu state dissociation were observed for 225.625 or 200.32 nm dissociation with O(3P2) detection, which implies that the O2 A'3Δu state dissociates exclusively to the third (O1D + O1D) dissociation limit. Dissociation is suggested to take place through the 21Πg upper state to the O1D + O1D limit where spin-orbit coupling of the A'3Δu state with the 11Πu state accesses the allowed parallel 1Πu → 1Πg transition. While the absence of a parallel-type photodissociation signal from the c1Σ-u state may be expected, the A3Σ+u should spin-orbit couple through the same pathway as the A'3Δu state. The fact that no clear A3Σ+u signal is observed suggests a faster deactivation process compared to the A'3Δu state in the discharge and ice desorption process.

A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi.

B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for ß-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. ß-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for ß-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to ß-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.

An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer.

The third-generation aromatase inhibitors (AIS) are largely replacing tamoxifen in the adjuvant treatment of early-stage breast cancer in postmenopausal women with hormone receptor-positive tumours. To date, multiple trials have been conducted comparing tamoxifen treatment with an AI, and all have demonstrated improved disease-free survival with AI treatment. Trials have included direct 5-year comparisons between tamoxifen and an AI, switching to an AI within 5 years after initial tamoxifen treatment, or extending treatment with an AI after 5 years of completed tamoxifen treatment. Some of these trials have been completed; others are ongoing; and head-to-head trial comparisons of individual AIS are also in progress. The present article summarizes the data obtained from various clinical trials of hormonal therapy for early breast cancer. It also reviews recent data so as to shed light on the current status of these therapies. The focus is on the efficacy of treatment with an AI. Toxicity is discussed in the second article in this supplement.

Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer.

Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European-Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin-paclitaxel regimen over cisplatin-cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin.

Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of angiostatin action remains unknown, identification of F(1)-F(O) ATP synthase as the major angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the angiostatin response. Previous studies noting the presence of F(1) ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F(1) ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by angiostatin as well as by antibodies directed against the alpha- and beta-subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics.

EORTC 10941: A phase II study of liarozole in postmenopausal patients with 'chemotherapy-resistant' or 'potentially hormone sensitive' metastatic breast cancer.

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: 'Chemotherapy Resistant' (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0-2 prior hormonal therapies) and 'Potentially Hormone Sensitive' (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150-300 mg orally bid. The objective response rate was 12% in the 'Chemotherapy Resistant' group (n = 34), and 22% in the 'Potentially Hormone Sensitive' group (n = 37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the 'ER negative' and 'Tamoxifen Refractory' groups will be reported in a future paper.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Vorozole (Rivizor): an active and well tolerated new aromatase inhibitor for the treatment of advanced breast cancer patients with prior tamoxifen exposure. Investigational Drug Branch of the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group.

Vorozole (Rivizor) is a potent and stereospecific inhibitor of aromatase having shown promising endocrine effects in phase I studies. In the present trial, 27 postmenopausal patients with advanced breast cancer, measurable lesions, presumably hormone responsive (ER or PR+, or ER? with disease-free survival longer than 1 year, or prior documented response to tamoxifen), were treated with vorozole one tablet 2.5 mg daily. All had been previously treated with tamoxifen as adjuvant (two patients) or for advanced disease (24 patients), or both (one patient). Objective remissions were observed in eight patients (30%) with two complete responses (CR) and six partial responses (PR) lasting for a median of 14.3 months (range 6.8-40.6); nine stabilizations were also recorded (median 7.9 months; range 3.7-40.1). Median time to progression for the 27 patients was 5.9 months. Sites of response were skin (three patients), lymph nodes (two patients), lung (two patients) and chest wall plus lymph nodes (one patient). Treatment was very well tolerated: mild hot flushes (four patients), gastrointestinal complaints (four patients) and no significant toxicity (common toxicity criteria grade above 2) or drug-related severe adverse event. It is concluded that vorozole is an active second-line endocrine treatment, deserving consideration for randomized comparison with other agents such as aminoglutethimide, megestrol acetate or medroxyprogesterone acetate.

Breast cancer therapies in development. A review of their pharmacology and clinical potential.

Although the management of breast cancer has improved over the past few decades, it remains an important challenge for the clinician. Cytotoxic chemotherapy and hormonotherapy, when given in the adjuvant setting, have a definitive though modest impact on the outcome of early-stage breast cancer. In metastatic disease, these therapies help to provide substantial palliation of symptoms but have a limited impact on survival. The discovery of vinorelbine and the taxanes, paclitaxel and docetaxel, certainly represented the most encouraging clinical development of the 1980s in breast cancer therapy. Several other new cytotoxic agents have been recognised for their potential in the treatment of this disorder. Many of them are only in a very early phase of their clinical development and it remains to be proven that they will have a major role in daily practice in the near future.

Adjuvant systemic therapy for breast cancer.

During the past year, the literature on adjuvant systemic therapy for breast cancer has focused on three main areas of interest. First, new information on biologic factors that might help in the determination of prognosis has been released but is still unlikely to have an impact on daily clinical practice. More important in this regard is the issuing by a consensus panel of practical recommendations for the treatment of node-negative breast cancer according to classic and well-validated prognostic and predictive factors. Second, new therapeutic strategies such as increasing the dose intensity of chemotherapy or incorporating new drugs into adjuvant regimens have been further explored. In addition, important new data regarding the optimal duration of tamoxifen administration in the adjuvant setting have been provided by a Swedish and a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial. Lastly, increased attention has been given to the toxicity of systemic adjuvant therapy, and new considerations such as preservation of quality of life have been taken into account.

An ongoing European organization for research and treatment of cancer crossover trial comparing single-agent paclitaxel and doxorubicin as first- and second-line treatment of advanced breast cancer.

The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in advanced breast cancer patients who have failed doxorubicin treatment is well established, but the optimal sequence between these two important agents remains to be determined. The European Organization for Research and Treatment of Cancer therefore designed a prospective randomized clinical trial in which patients not exposed to anthracyclines in the adjuvant setting received either first-line paclitaxel, given as a 3-hour infusion at a dose of 200 mg/m2 followed at the time of disease progression by second-line doxorubicin, given as a bolus injection at a dose of 75 mg/m2 or the reverse sequence. The target accrual is 330 patients. Interim results on 207 evaluable patients of 289 randomized are presented.

[Systemic adjuvant therapy of breast cancer: myths and controversies]. / La thérapie adjuvante systémique du cancer du sein: mythes et controverses.

The value of adjuvant systemic therapy in breast cancer patients is well established but remains essentially modest. Operable breast cancer patients with positive or negative axillary lymph nodes, will have a 20% decrease in their annual odds of death at 10 years with appropriate systemic therapy. Several questions are still open in the field of systemic adjuvant therapy. For patients with node negative disease, treatment recommendations were recently issued by a group of experts with the aim to percent over- and under-treatment. The optimal duration of tamoxifen adjuvant therapy is still debatable, as is its role in a prevention setting. In patients with 10 or more positive axillary nodes, the search for more effective therapies prompted investigators to compare standard dose chemotherapy to high dose chemotherapy. Also, the value of adding a taxoid in the adjuvant chemotherapy regimen, is tested by several research groups. Hopefully, some of these hypothesis will be translated into a greater benefit for each individual breast cancer patient.

Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

PURPOSE: To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD: A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS: None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION: In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.

Adjuvant systemic therapy for breast cancer.

The continued research efforts in the field of breast cancer adjuvant therapy are translating into a better understanding of the real, but still modest, impact on patient outcome. Recent publications are focusing either on secondary leukemias or on secondary solid tumors, which are associated with the use of adjuvant chemotherapy or adjuvant tamoxifen, respectively. These attempts at an improved risk-benefit assessment of classic adjuvant treatment for breast cancer are to be encourage. In parallel, there is an urgent need for innovative treatment approaches that have to be carefully evaluated through prospective randomized clinical trials. These include increasing chemotherapy dose intensity, changing timing or scheduling of drug administration, or moving new active agents, such as the taxoid compounds, to the adjuvant setting. Major efforts still need to be done in using new molecular markers of tumor aggressiveness for an improved assessment of a patient's individual risk of relapse. Finally, increasing attention is being paid to optimal therapy for elderly patients.

[Respective indications for hormone therapy, induction chemotherapy and adjuvant chemotherapy in breast cancer without clinically discernable distant metastases]. / Indications respectives de l'hormonothérapie, de la chimiothérapie d'induction et de la chimiothérapie adjuvante dans le cancer du sein sans métastases à distance cliniquement décelables.

Adjuvant therapy for breast cancer is an effective mean to reduce the likelihood of recurrence and to increase overall survival, as shown by the Early Breast Cancer Trialists' Group Overview. Although these benefits are clearly significant, they represent a modest improvement in the care of breast cancer. The role of pre-operative chemotherapy remains to be defined in early stage breast cancer. Otherwise, pre-operative chemotherapy has become 'standard of care' in locally advanced and inflammatory breast cancer. There are still several questions to be answered in the field of adjuvant and pre-operative chemotherapy. Prospective randomized clinical studies are the only way to obtain further therapeutic progress for this highly lethal disease.