Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.     

Comparing quality of life following liver transplantation for Laennec's versus non-Laennec's patients

The overall success of orthotopic liver transplantation (OLTX) includes not only survival, but quality of life (QOL) as well. We studied one controversial group of OLTX recipients, patients transplanted for alcoholic liver disease (Laennec's), to determine if their post-OLTX QOL was similar to that of patients transplanted for non-alcoholic liver disease (non-Laennec's). Over a 10-yr period, patients undergoing OLTX at our institution were asked to complete a QOL questionnaire addressing a wide range of topics from demographics and employment to symptom distress/frequency, activities of daily living, and effect of loss of health on daily life. Twenty-four Laennec's and 100 non-Laennec's OLTX recipients completed the questionnaire at both their 2- and 5-yr follow-up visits at our institution. Both groups were well-matched in age, race, and patient location status at the time of OLTX. No significant differences could be detected between Laennec's and non-Laennec's scores regarding overall QOL, including one's ability to function, health perception, and self-perception at 2 and 5 years post-OLTX, and between 2 and 5 years post-OLTX. Although not between groups, a significant difference was noted regarding patients' satisfaction with life, with less satisfaction reported at the 5-yr versus the 2-yr time point post-OLTX. Rates of current/recent employment between both groups were also similar at 2 years post-OLTX, and again at 5 years post-OLTX. We conclude that overall QOL and employment levels appear similar between patients transplanted for alcoholic and non-alcoholic liver disease. This similarity appears to extend to 5 years post-OLTX.     

Implementing and maintaining school-based mental health services in a large, urban school district

The Dallas (Texas) Public Schools established the first school-based health center in the United States in 1969. In 1993 a partnership between two school principals, a school mental health professional, and the medical director of the county mental health center was the impetus for the first comprehensive school-based mental health center in Texas. In 1995 the programs joined together as Youth and Family Centers (YFCs) to provide physical health, mental health, and other support services to students and their families. The 10 strategically located school-based centers are directed by licensed mental health professionals employed by the district who lead a multidisciplinary team of physical health and mental health providers. Students served by the YFCs have fewer discipline problems, course failures, and school absences.     

Comparison of recoveries in breath carbon dioxide of H13CO-3 and H14CO-3 administered simultaneously by single 6 h constant unprimed intravenous infusion

The aim of this study was to assess the bioequivalence of H13CO-3 and H14CO-3, by administering both labels simultaneously by single infusion and comparing their recovery in breath CO2 and urinary urea. Six healthy male subjects (age range 24-41 years; weight 76.7 (sd, 18.6) kg; height 1.79 (sd 0.05) m) were infused with unprimed solutions of HCO3- (110.0 mmol/kg) labelled with 13C (0.76 mmol 13C/h) and 14C (48 Bq/h) at a constant rate for 6 h, in a whole-body calorimeter (1400 litres) for measurement of CO2 production. Samples of breath were collected hourly in a Douglas bag and all urine was collected into two batches (0-4 h and 4-6 h) for estimating recovery of infused label by measurement of enrichment or specific activity. Recovery in breath CO2 of both labels increased from about 25 % for the first hour to 88 % and above for hours 3-4 onwards. Mean recovery of 13C in breath CO2 was slightly higher than that of 14C for all periods (mean difference always less than 1 % of infused label) but was significant only for the first 3 h (P < 0.05). Recovery of 14C in urea was significantly higher (P < 0.01) than 13C, but was confounded by substantial variability and uncertainties concerning 13CO2 background enrichments. These results suggest that there is no compelling need to alter factors currently used for recovery of 14C in breath when using 13C instead, and vice versa.     

Immediate hip spica casting for femur fractures in pediatric patients. A review of 175 patients

Immediate closed reduction and application of a well-molded hip spica cast is a safe and effective treatment option for closed, isolated femur fractures in children who weigh between 10 and 100 pounds. Between 1988 and 1996, 190 immediate hip spica casts were placed on children with isolated femoral shaft fractures who weight between 10 and 100 pounds. Fifteen patients were lost to followup leaving 175 children who were evaluated and followed up for at least 2 years after the hip spica cast was removed (range 2-10 years). The femur fractures were reduced closed and placed in a 1 1/2 hip spica cast in the emergency room with the patient under conscious sedation or in the operating room with the patient under general anesthesia. All of the children returned home within 24 hours of the procedure. All 175 femur fractures united within 8 weeks. The only complication was a refracture in a 25 pound child who fell 1 week after the cast was removed. No significant residual angular deformities were present in any of the children at last followup. None of the children required external shoe lifts, epiphysiodesis, antibiotics, irrigation and debridements, or limb lengthening procedures for leg length inequalities. The authors think that immediate closed reduction and placement of a well-molded hip spica cast is a safe and reliable treatment option for isolated, closed femur fractures in children from birth to 10 years of age who weigh less than 80 pounds.     

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.     

Adapting the multilevel model for estimation of the reliable change index (RCI) with multiple timepoints and multiple sources of error

ObjectiveOne of the primary tools in the assessment of individual‐level patient outcomes is Jacobson and Truax, (1991’s) Reliable Change Index (RCI). Recent efforts to optimize the RCI have revolved around three issues: (a) extending the RCI beyond two timepoints, (b) estimating the RCI using scale scores from item response theory or factor analysis and (c) estimation of person‐ and time‐specific standard errors of measurement.MethodWe present an adaptation of a two‐stage procedure, a measurement error‐corrected multilevel model, as a tool for RCI estimation (with accompanying Statistical Analysis System syntax). Using DASS‐21 data from a community‐based mental health center (N = 379), we illustrate the potential for the model as unifying framework for simultaneously addressing all three limitations in modeling individual‐level RCI estimates.ResultsCompared to the optimal‐fitting RCI model (moderated nonlinear factor analysis scoring with measurement error correction), an RCI model that uses DASS‐21 total scores produced errors in RCI inferences in 50.8% of patients; this was largely driven by overestimation of the proportion of patients with statistically significant improvement.ConclusionEstimation of the RCI can now be enhanced by the use of latent variables, person‐ and time‐specific measurement errors, and multiple timepoints.     

Recommendations for Better Civic Learning: Building and Rebuilding Democracy

This is the concluding essay for a special report from The Hastings Center entitled Democracy in Crisis: Civic Learning and the Reconstruction of Common Purpose, which grew out of a project supported by the John S. and James L. Knight Foundation. This essay provides an integrative discussion of various theoretical and practical reform perspectives offered by other essays in the report. It also offers a number of recommendations. It notes that the aim of the special report is not to propose specific reform measures but, rather, to consider larger, more theoretic concerns related to political and economic questions, which are personal and structural—psychological, cultural, and institutional—at the same time. In response, this essay argues that the best relationship between the citizenry and government in a democracy is not one of deference, nor one of contestation, but one that is critically constructive, which in turn is linked to practices of civic learning. To be constructive, citizens need scientific literacy, an understanding of how government and other institutions work, critical thinking abilities, and many open and diverse forums for civic learning to offset the increasingly isolating media “bubbles” that are the only source of information for many. The essay then formulates five recommendations designed to facilitate critically constructive citizenship and civic learning. These are creating a basis for civic participation, acquiring information, talking to each other, designing institutional change, and achieving deliberation.