Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness.

Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Multiple matrix metalloproteinases (MMPs), known to remodel extracellular matrix, are expressed by AML cells and the BM microenvironment. We reason MMPs could be involved in cell displacement and vascular leakiness; therefore, we evaluate the therapeutic potential of MMP pharmacological inhibition using the broad-spectrum inhibitor prinomastat. IVM analyses of prinomastat-treated mice reveal reduced vascular permeability and healthy cell clusters in circulation and lower AML infiltration, proliferation, and cell migration. Furthermore, treated mice have increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Analysis of a human AML transcriptomic database reveals widespread MMP deregulation, and human AML cells show susceptibility to MMP inhibition. Overall, our results suggest that MMP inhibition could be a promising complementary therapy to reduce AML growth and limit HSPC loss and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.

BACKGROUND: New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS: We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS: In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302 < CYM-52288 < CYM-52220 << JDTic. Furthermore, LY-2456302 blocked the depressive (anhedonia-producing) effects of the kappa opioid receptor agonist U50,488 in the intracranial self-stimulation paradigm, albeit at a higher dose than that needed for analgesic blockade in the tail flick assay. CONCLUSIONS: These results suggest that structurally diverse kappa opioid receptor antagonists can have short-acting effects and that LY-2456302 reduces anhedonia as measured in the intracranial self-stimulation test.

Body composition at high altitude: a randomized placebo-controlled trial of dietary carbohydrate supplementation.

BACKGROUND: Body mass loss is inevitable with chronic hypoxic exposure. However, the exact body-composition changes, their causes, and possible treatments remain unknown. OBJECTIVE: The objective was to investigate body composition during a high-altitude expedition by using non-empirically derived methods, experimentally manipulating energy intake, and investigating the influence of initial body composition. DESIGN: Forty-one participants completed a 21-d expedition in the Himalayas. Energy intake was manipulated with a double-blind, placebo-controlled, randomized trial of carbohydrate energy supplementation. Body composition was assessed before and after the expedition by using a 4-component model including fat mass, total body water, bone mineral mass, and residual mass (principally protein and glycogen). Data were analyzed by repeated-measures analysis of variance. RESULTS: Participants allocated to receive carbohydrate were given an additional 15,058 +/- 6211 kcal over the 21-d expedition (>6 kcal x kg(-1) x d(-1)). Nevertheless, the functionally important residual mass decreased in both groups by 6% (main effect of time: P = 0.021), with no effect of allocation (interaction effect: P = 0.116). Similar decreases were observed for fat mass (11%) and total body water (3%), which were also unabated by allocation. Furthermore, high initial fat mass (by median split) did not preserve residual mass (high-fat compared with low-fat participants: residual loss = 5% compared with 8%; P = 0.990). CONCLUSIONS: High-altitude exposure decreased body mass, including the functionally important residual component. These losses were not abated by increasing energy intake or an initially high fat mass. Factors other than negative energy balance must contribute to body-composition changes with chronic hypoxia. This trial was registered at clinicaltrials.gov as NCT00731510.

Manipulation under anesthesia: a report of four cases.

OBJECTIVE: To report the results of manipulation under anesthesia (MUA) for 4 patients with chronic spinal, sacroiliac, and/or pelvic and low back pain. METHODS: The treatment group was arbitrarily selected from the chiropractor's patient base who received the MUA protocol along with a follow-up in-office articular and myofascial release program that mimics the MUA procedures. The chiropractic adjustments and articular and myofascial release procedures were performed in a chiropractic office. The MUA procedures were performed in an outpatient ambulatory surgical center. Patients with chronic pain who had not adequately responded to conservative medical and/or a reasonable trial (4 months minimum) of chiropractic adjustments, and had no contraindications to anesthesia or adjustments, were selected. The 4 patients went through 3 consecutive days of MUA followed by an 8-week protocol of the same procedures plus physiotherapy in-office without anesthesia. Data included pre- and post-MUA passive ranges of motion, changes in the visual analog scale, and neurologic and orthopedic examination findings. The patients had follow-up varying from 9 to 18 months. RESULTS: Increases in passive ranges of motion, decreases in the visual analog scale rating, and diminishment of subsequent visit frequency were seen in each of the patients. CONCLUSION: Manipulation under anesthesia was an effective approach to restoring articular and myofascial movements for these 4 patients who did not adequately respond to either medical and/or in-office conservative chiropractic adjustments and adjunctive techniques.

Lead generation--enhancing the success of drug discovery by investing in the hit to lead process.

Improving on the poor success rates in the drug discovery industry requires that knowledge-based decisions are made to advance or stop a lead candidate as early as possible in the discovery process. Failure to make such timely decisions on the rigorous selection of lead candidates has costly time and resource implications in downstream drug development. To meet this challenge dedicated 'hit to lead' groups have recently been established in many major pharmaceutical companies, and a key to the success of such groups is establishing a clear consistent process and rigorous metrics for lead quality. The importance of such a "Lead Generation" group within the drug discovery process will be highlighted with the aim of placing a greater level of emphasis in discovering and refining novel lead series with enhanced drug-like properties. This activity is facilitated by the application of productivity enhancing, integrated technologies coupled with the early evaluation of drug-like properties in the lead refinement process to ensure that a balanced activity - properties profile can be attained before committing to a full lead optimisation program. This article will survey the processes and tools employed in the hit to lead process in such a "Lead Generation" group in order to achieve these objectives, emphasising the possible gains in productivity through close, early interactions between chemistry and other expert groups.