Osteoarticular and muscle infectious lesions in patients with the human immunodeficiency virus

Summary Between 1988 and 1995, 1832 HIV positive patients were evaluated in our institution. We studied the epidemiologic, immunologic and bacteriologic data, laboratory tests, and X-Ray films in those with musculoskeletal infection. We reviewed twenty-one cases of musculoskeletal infection in twenty patients aged 23–35 years (mean 28,6 years, M:F=15:5). In all of them risk factor for HIV was intravenous drug abuse. The number of CD4 positive lymphocytes ranged from 0,003 to 0,5 10⁹/l. Staphylococcus aureus was the organism responsible of the infection in twelve cases, all active intravenous drug abusers at the time the diagnosis was done. The remaining causative agents were: Mycobacterium tuberculosis (3 cases), Candida albicans (2 cases), Salmonella subgroup 1 (1 case), Neisseria gonorrhoeae (1 case), Pseudomona aeruginosa (1 case) and Streptococcus agalactiae (1 case). Fifteen infections were diagnosed between 1988 and 1991 and 6 between 1992 and 1995. Musculoskeletal infectious lesions in HIV positive patients in our country are related in the majority of cases to intravenous drug abuse. In the last four years due to a National medical health care plan conducted to educate this group of people the number of musculoskeletal infections is decreasing.     

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.     

Evaluation of micro-CT for emphysema assessment in mice: comparison with non-radiological techniques

Objectives

To define the potential, limitations and synergies of micro-CT and other non-radiological techniques for the quantification of emphysema and related processes in mice, by performing a complete characterization of the elastase-induced emphysema model.

Materials and methods

Ninety A/J mice (45 treated and 45 controls) were studied at different time points using breath-hold gated micro-CT, functional test parameters, RT-PCR for RNA cytokine expression, Luminex technology for cytokine plasma concentration and histomorphometry.

Results

Both histomorphometry and micro-CT imaging reflect rapid initial emphysema progression followed by steady-state development at decreasing rates. Cytokine measurements reveal an acute inflammatory response within the first 24?h that disappears after the first week. Limited systemic effect was observed based on plasma cytokine concentration. Lung compliance decreases during the acute inflammation phase and increases afterwards.

Conclusion

Histomorphometry is the most sensitive technique since it detects airspace enlargement before the other methods (1?h after treatment). Micro-CT correlates well with histology (r2?=?0.63) proving appropriate for longitudinal studies. Functional test parameters do not necessarily correlate with the extent of emphysema, as they can be influenced by acute inflammation. Finally, cytokine measurements correlate with the presence of inflammation in histology but not with emphysema.     

Longitudinal study of a mouse model of chronic pulmonary inflammation using breath hold gated micro-CT

Objectives  

To evaluate the feasibility of using automatic quantitative analysis of breath hold gated micro-CT images to detect and monitor disease in a mouse model of chronic pulmonary inflammation, and to compare image-based measurements with pulmonary function tests and histomorphometry.     

Plasma folate concentrations after a single dose ingestion of whole and skimmed folic acid fortified milks in healthy subjects

Background  

Since mandatory folic acid fortification of grains and cereals was introduced in order to prevent neural tube defects, the number of products that are being fortified with folic acid is growing, especially milk and dairy products. However, the effectiveness of this action remains controversial.     

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer

Background.

In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial.

Patients and Methods.

We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2).

Results.

A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2− and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%.

Conclusion.

Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis.

Implications for Practice:

The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.