Enhanced triplet superconductivity in next-generation ultraclean UTe2.

The unconventional superconductor UTe[Formula: see text] exhibits numerous signatures of spin-triplet superconductivity-a rare state of matter which could enable quantum computation protected against decoherence. UTe[Formula: see text] possesses a complex phase landscape comprising two magnetic field-induced superconducting phases, a metamagnetic transition to a field-polarized state, along with pair- and charge-density wave orders. However, contradictory reports between studies performed on UTe[Formula: see text] specimens of varying quality have severely impeded theoretical efforts to understand the microscopic origins of the exotic superconductivity. Here, we report a comprehensive suite of high magnetic field measurements on a generation of pristine quality UTe[Formula: see text] crystals. Our experiments reveal a significantly revised high magnetic field superconducting phase diagram in the ultraclean limit, showing a pronounced sensitivity of field-induced superconductivity to the presence of crystalline disorder. We employ a Ginzburg-Landau model that excellently captures this acute dependence on sample quality. Our results suggest that in close proximity to a field-induced metamagnetic transition the enhanced role of magnetic fluctuations-that are strongly suppressed by disorder-is likely responsible for tuning UTe[Formula: see text] between two distinct spin-triplet superconducting phases.

Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus.

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3-8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. TRIAL REGISTRATION: NCT01025817.

Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

A web-based application for initial screening of living kidney donors: development, implementation and evaluation.

Most centers utilize phone or written surveys to screen candidates who self-refer to be living kidney donors. To increase efficiency and reduce resource utilization, we developed a web-based application to screen kidney donor candidates. The aim of this study was to evaluate the use of this web-based application. Method and time of referral were tabulated and descriptive statistics summarized demographic characteristics. Time series analyses evaluated use over time. Between January 1, 2011 and March 31, 2012, 1200 candidates self-referred to be living kidney donors at our center. Eight hundred one candidates (67%) completed the web-based survey and 399 (33%) completed a phone survey. Thirty-nine percent of donors accessed the application on nights and weekends. Postimplementation of the web-based application, there was a statistically significant increase (p < 0.001) in the number of self-referrals via the web-based application as opposed to telephone contact. Also, there was a significant increase (p = 0.025) in the total number of self-referrals post-implementation from 61 to 116 per month. An interactive web-based application is an effective strategy for the initial screening of donor candidates. The web-based application increased the ability to interface with donors, process them efficiently and ultimately increased donor self-referral at our center.

CHALLENGES IN MANAGEMENT OF WARFARIN ANTI-COAGULATION IN ADVANCED HIV/AIDS PATIENTS WITH VENOUS THROMBOTIC EVENTS--A CASE SERIES FROM A RESEARCH CLINIC IN RURAL KERICHO, KENYA.

BACKGROUND: Venous thrombotic events (VTE) occur at high ratesin HIV/AIDS patients and are likely under-diagnosed in rural sub-Saharan Africa. OBJECTIVE: To describe clinical presentations and challenges in the management of VTE in patients with advanced HIV/AIDS. DESIGN: Case series from patients enrolled in a prospective observational cohort study. SETTINGS: A clinical research centre in rural Kericho, Kenya. SUBJECTS: Two hundred patients with median age 38 (30-47) years, BMI 16.9 (12.4-20.3) kg/m2, haemoglobin 9.3 (6.8-13.4) g/dL, CD4+ T-cell count 27 (4-77) cells/mm and plasma HIV RNA 5.23 (3.70-5.88) log10 copies/mL. INTERVENTIONS: VTE cases were diagnosed by clinical presentation and Doppler/ radiographic confirmation. Anti-coagulation therapy was managed by a multidisciplinary team; patients were initiated on enoxaparin or heparin followed by warfarin. RESULTS: Over two years,11patients (5.5%) experienced VTE. All but one (10/11,90.9%) case occurred within six months of starting ART. Nine patients had peripheral VTE (five popliteal, four femoral) and two had cerebral sinus thromboses. VTE was diagnosed 52 (1-469) days after ART initiation, and 81.8% of cases were outpatients at presentation. All patients received at least one concomitant medication that could significantly interact with warfarin (efavirenz, nevirapine, lopinavir/ritonavir, rifampicin, trimethoprim-sulfamethoxazole, and fluconazole). A median of 39 (10-180) days and eight (4-22) additional clinic visits were required to achieve/maintain a therapeutic INR of 2-3. Two minor bleeding complications occurred. No recurrent VTE cases were observed. CONCLUSION: Consideration of VTE and preparedness for management in patients with advanced HIV/AIDS starting ART is critical in sub-Saharan Africa. Overcoming challenges in anti-coagulation is possible in rural settings using a multidisciplinary team approach.

Development and validation of technologies suitable for the decontamination and re-use of contaminated N95 filtering facepiece respirators in response to the COVID-19 pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has brought significant challenges to society globally, particularly in the area of healthcare provision. A pressing need existed in protecting those tasked with delivering healthcare solutions during the COVID-19 crisis by providing solutions for preserving adequate supplies of effective personal protective equipment (PPE). AIM: To evaluate and validate available methods for the decontamination of N95 filtering facepiece respirators (FFRs) while maintaining functionality during re-use. METHODS: Multiple low-temperature steam and vaporized hydrogen peroxide (VHP) technologies were assessed for inactivation of Mycobacterium spp. and feline calicivirus (employed as representatives of the contamination challenge). FINDINGS: Virus (≥3log10) and Mycobacterium spp. (≥6log10) inactivation was achieved on various types of N95 FFRs using an array of heat (65-71oC), humidity (>50% relative humidity) and VHP without affecting the performance of the PPE. CONCLUSION: The methods have been validated and were authorized by the US Food and Drug Administration under a temporary emergency use authorization. Based on the findings, opportunities exist for development and deployment of decontamination methods made from simple, general purpose materials and equipment should a future need arise.

The antibody response to specific immune complexes is under genetic control and correlates with the expression of a recurrent idiotype.

The primary antigen-specific antibody response of various strains of mice to TEPC-15/PnC immune complexes has been examined. We found that both BALB/c and C3H mice were good responders to the PnC antigen; however, C3H mice were low responders, whereas BALB/c mice were high responders to the TEPC-15/PnC complexes. Using congenic strains on the C3H and BALB/c background, we have shown that the response to the complexes is not restricted by gene products of the H-2 complex or by the Igh (allotype) locus. However, responsiveness may be controlled by genes linked to the Igh locus, since we have shown that strains that are Ighj, Ighd, and Ighf are low responders, whereas strains that are Igha, Ighb, and Ighe are high responders to the immune complex. Moreover, responsiveness correlates with the expression of the T15 Id as measured using the anti-T15 monoclonal antibody, AB1-2. Thus, strains such as BALB/c, BALB.B, BALB.K, and CB-20, which express high levels of T15 (AB1-2) Id in their PFC response to PnC are relatively high responders to TEPC-15/PnC complexes, whereas C3H, C3H.SW, and C3H-OH, which express low levels of the T15 (AB1-2) Id, are low responders to the complexes. Finally, we found that BALB/c mice are high responders to complexes formed with T15+ antibodies, whereas they are low responders to complexes formed using T15- antibodies. The results suggest that the antigen-specific response to these immune complexes is Id-restricted.

How baseball outfielders determine where to run to catch fly balls.

Current theory proposes that baseball outfielders catch fly balls by selecting a running path to achieve optical acceleration cancellation of the ball. Yet people appear to lack the ability to discriminate accelerations accurately. This study supports the idea that outfielders convert the temporal problem to a spatial one by selecting a running path that maintains a linear optical trajectory (LOT) for the ball. The LOT model is a strategy of maintaining "control" over the relative direction of optical ball movement in a manner that is similar to simple predator tracking behavior.

Very-Long-Baseline Radio Interferometry: The Mark III System for Geodesy, Astrometry, and Aperture Synthesis.

The Mark III very-long-baseline interferometry (VLBI) system allows recording and later processing of up to 112 megabits per second from each radio telescope of an interferometer array. For astrometric and geodetic measurements, signals from two radio-frequency bands (2.2 to 2.3 and 8.2 to 8.6 gigahertz) are sampled and recorded simultaneously at all antenna sites. From these dual-band recordings the relative group delays of signals arriving at each pair of sites can be corrected for the contributions due to the ionosphere. For many radio sources for which the signals are sufficiently intense, these group delays can be determined with uncertainties under 50 picoseconds. Relative positions of widely separated antennas and celestial coordinates of radio sources have been determined from such measurements with 1 standard deviation uncertainties of about 5 centimeters and 3 milliseconds of arc, respectively. Sample results are given for the lengths of baselines between three antennas in the United States and three in Europe as well as for the arc lengths between the positions of six extragalactic radio sources. There is no significant evidence of change in any of these quantities. For mapping the brightness distribution of such compact radio sources, signals of a given polarization, or of pairs of orthogonal polarizations, can be recorded in up to 28 contiguous bands each nearly 2 megahertz wide. The ability to record large bandwidths and to link together many large radio telescopes allows detection and study of compact sources with flux densities under 1 millijansky.

The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity.

Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation-sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non-lymphoid cells. We also show that B-lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers.

ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression.

The interaction between stromal cells and tumor cells is emerging as a critical aspect of tumor progression. Yet there is a paucity of molecular markers for cells participating in such interactions, and only few genes are known to play a critical role in this process. Here, we describe the identification of ADAM12 (a disintegrin and metalloprotease 12) as a novel marker for a subpopulation of stromal cells that are adjacent to epithelial tumor cells in three mouse carcinoma models (models for prostate, breast and colon cancer). Moreover, we show that ADAM12 is essential for tumor development and progression in the W10 mouse model for prostate cancer. These results suggest that ADAM12 might be a useful marker for stromal cells in mouse tumors that are likely to participate in stromal/tumor cell crosstalk, and that ADAM12 is a potential target for design of drugs that prevent carcinoma growth.

A2 to B Blood Type Incompatible Deceased Donor Kidney Transplantation in a Recipient Infected with the Human Immunodeficiency Virus: A Case Report.

BACKGROUND: With the introduction of the Kidney Allocation System in the United States in December 2014, transplant centers can list eligible B blood type recipients for A2 organ offers. There have been no prior reports of ABO incompatible A2 to B deceased donor kidney transplantation in human immunodeficiency virus-positive (HIV+) recipients to guide clinicians on enrolling or performing A2 to B transplantations in HIV+ candidates. We are the first to report a case of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results. METHODS AND RESULTS: We describe an HIV+ 39-year-old African American man with end-stage renal disease who underwent A2 to B blood type incompatible deceased donor kidney transplantation. Prior to transplantation, he had an undetectable HIV viral load. The patient was unsensitized, with his most recent anti-A titer data being 1:2 IgG and 1:32 IgG/IgM. Induction therapy of basiliximab and methylprednisolone was followed by a postoperative regimen of plasma exchange, intravenous immunoglobulin, and rituximab with maintenance on tacrolimus, mycophenolate mofetil, and prednisone. He had delayed graft function without rejection on allograft biopsy. Nadir serum creatinine was 2.0 mg/dL. He continued to have an undetectable viral load on the same antiretroviral therapy adjusted for renal function. CONCLUSIONS: To our knowledge, this is the first report of A2 to B deceased donor kidney transplantation in an HIV+ recipient with good intermediate-term results, suggesting that A2 donor kidneys may be considered for transplantation into HIV+ B-blood type wait list candidates.

Calcineurin inhibitor avoidance versus steroid avoidance following kidney transplantation: Postoperative complications.

This study compared early postoperative complications in kidney transplant recipients treated with either a sirolimus-based calcineurin inhibitor (CNI)-free regimen or a tacrolimus-based steroid-free regimen. We used a single-center, prospective, sequential but nonrandomized study design. Consecutive recipients of primary cadaveric or non-HLA identical kidney transplant recipients received either a CNI-free regimen, consisting of sirolimus 5 mg daily beginning postoperative day 3, mycophenolate mofetil 1 gm twice a day, and methylprednisolone 500 mg intraoperatively, then prednisone 30 mg daily tapered to 10 mg daily at 3 months, or a prednisone-free regimen, consisting of methylprednisolone 500 mg, 250 mg, and 125 mg from days 0 to 2, then no further steroids, tacrolimus 0.075 mg/kg twice a day, and mycophenolate mofetil 1 g twice a day. All patients received thymoglobulin induction 6 mg/kg total dose. Outcome measures were patient and graft survival, BPAR, surgical and wound complications, viral infections and posttransplant diabetes mellitus (PTDM). Both groups had excellent early outcomes with no significant difference in patient or graft survival, early renal function, BPAR, surgical or wound complications, or viral infections between the two groups. Patients in the sirolimus-based CNI-free group had a significantly higher incidence of PTDM and a trend toward more discontinuation due to drug toxicity. Whether either regimen improves long-term outcomes awaits longer follow-up.

Short-term results under three different immunosuppressive regimens at one center.

We examined short-term outcomes and posttransplant medical complications under three different immunosuppressive regimens at a single center. The study design was a randomized, prospective, open-label trial comparing a calcineurin inhibitor-free (CNI) protocol to standard triple therapy with tacrolimus, prednisone, and mycophenolate mofetil. They were also compared to a concurrent but nonrandomized third cohort treated with a prednisone-free protocol. All three groups had excellent early outcomes with no significant difference in patient or graft survival or biopsy-proven acute rejection. Serum creatinine was significantly lower in the CNI-free recipients. Lipid panels and posttransplant diabetes mellitus were significantly lower in the prednisone-free patients. Prednisone-free kidney transplant recipients have improved early glucose metabolism and hyperlipidemia compared to CNI-free or standard triple therapy recipients with comparable rejection and graft survival rates.

Characteristics of HIV infected patients cared for at "academic model for the prevention and treatment of HIV/AIDS" clinics in western Kenya.

BACKGROUND: With the new initiatives to treat large numbers of HIV infected individuals in sub-Saharan Africa, policy makers require accurate estimates of the numbers and characteristics of patients likely to seek treatment in these countries. OBJECTIVE: To describe characteristics of adults receiving care in two Kenyan public HIV clinics. DESIGN: Cross-sectional cohort analysis of data extracted from an electronic medical records system. SETTING: Academic Model for the Prevention and Treatment of HIV/AIDS (AMPATH) HIV clinics in Kenya's second national referral (urban) hospital and a nearby rural health center. SUBJECTS: Adult patients presenting for care at HIV clinics. MAIN OUTCOME MEASURES: Gender and inter-clinic stratified comparisons of demographic, clinical, and treatment data. RESULTS: In the first nineteen months, 790 adults visited the urban clinic and 294 the rural clinic. Mean age was 36 +/- 9 (SD) years. Two-thirds were women; a quarter had spouses who had died of acquired immune deficiency syndrome (AIDS). HIV/AIDS behavioural risk factors (multiple sexual partners, rare condom use) and constitutional symptoms (fatigue, weight loss, cough, fever, chills) were common. Rural patients had more symptoms and less prior and current tuberculosis. Men more commonly presented with symptoms than women. The cohort CD4 count was low (223 +/- 197 mm3), with men having significantly lower CD4 count than women (185 +/- 175 vs. 242 +/- 205 p = 0.0007). Eighteen percent had an infiltrate on chest radiograph. Five percent (most often men) had received prior antiretroviral drug therapy, (7% in urban and 1% in rural patients, p = 0.0006). Overall, 393 (36%) received antiretroviral drugs, 89% the combination of lamivudine, stavudine, and nevirapine. Half received prophylaxis for tuberculosis and Pneumocystis jirovecii. Men were sicker and more often received antiretroviral drugs. CONCLUSIONS: Patients presenting to two Kenyan HIV clinics were predominantly female, ill and naive to retroviral therapy with substantial differences by clinic site and gender. Behavioural risk factors for HIV/AIDS were common. A thorough understanding of clinical and behavioural characteristics can help target prevention and treatment strategies.

A randomized phase I trial of chronic oral etoposide with or without granulocyte-macrophage colony-stimulating factor in patients with advanced malignancies.

Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 micrograms/kg/day s.c. days 1-10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days -6 to -2). VP16 was begun at 25 mg/m2/day on level 1 and increased to 50 mg/m2/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm3 and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm3. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.

Tissue distribution of three members of the murine protein disulfide isomerase (PDI) family.

The distribution of PDI, ERp61 and ERp72, members of the protein disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins, was determined in various murine tissues. Relative amounts of mRNA were measured using a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. Protein levels were determined from Western blots. In most tissues, protein levels paralleled the amount of mRNA for each PDI family member. The tissue distribution of the PDI and ERp72 mRNAs was similar, although ERp72 was not as abundant as PDI in the tissues. The tissue distribution of the ERp61 mRNA was significantly different from the two other family members. To help define potential hormonal or maturational differences in the regulation of expression of PDI family members, mRNA was measured in the frontal cortex, liver, pituitary gland and uterus at timed intervals during postnatal maturation. Except in the pituitary gland, the mRNA levels at 10 days and 22 days after birth were essentially identical to those in the adult. The ERp61 and ERp72 mRNAs were present at 2- to 3-fold higher levels in the pituitary glands of the 10- and 22-day-old mice, than in the adult mice. In addition, the pituitary gland PDI mRNA was 2- to 3-fold higher in 10-day-old mice than in adults. In general, levels of PDI family members were higher in secretory tissues than in other tissues in both immature and adult mice.

Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion.

PURPOSE: To determine the potential efficacy and dose-limiting toxicity of taxotere, a hemisynthetic inhibitor of tubulin depolymerization. PATIENTS AND METHODS: Fifty-eight patients were administered taxotere in this phase I clinical trial as a 6-hour or a 2-hour infusion repeated every 21 days. Forty patients received 181 courses on the 6-hour infusion schedule, and 18 patients received 105 courses on the 2-hour infusion schedule. RESULTS: Neutropenia was the dose-limiting toxicity on both schedules. The maximally tolerated dose was 100 mg/m2 on the 6-hour infusion schedule and 115 mg/m2 on the 2-hour infusion schedule. The most prominent nonhematologic toxicities included mucositis (more prominent on the 6-hour infusion schedule), transient rash (more common on the 2-hour infusion schedule), and alopecia. Hypersensitivity reactions were seen in five patients. There was no evidence of neurotoxicity or cardiotoxicity. One partial response was noted on the 6-hour infusion schedule (one in refractory breast cancer) and four additional partial responses were noted on the 2-hour infusion schedule (two in adenocarcinoma of the lung, one in refractory breast cancer, one in cholangio-carcinoma). In addition, 10 patients had minor responses. Pharmacokinetic studies showed plasma concentrations of taxotere declined in a triexponential manner, with a terminal half-life of 11.8 hours. CONCLUSION: The recommended starting dose for phase II taxotere trials is 100 mg/m2 administered as a 2-hour infusion, repeated every 21 days. Taxotere is a promising antineoplastic agent worthy of extensive phase II testing in patients with a variety of malignancies.