Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) that progresses on androgen receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase 1 multicenter study of BMS-986365 in patients with progressive mCRPC. PATIENTS AND METHODS: Patients who progressed on androgen deprivation therapy, ≥ 1 ARPI, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (Part A) and expansion (Part B) of BMS-986365 up to 900 mg twice daily (BID). Primary objectives were safety, tolerability, and to define maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS). RESULTS: Parts A and B enrolled 27 and 68 patients, respectively. In Part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events (TRAEs) were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A MTD was not reached and RP2D selection is ongoing. Across Part B three highest doses (400-900 mg BID, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% CI) was 6.3 months (5.3-12.6), including 8.3 months (3.8-16.6) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5-not evaluable) versus 5.5 months (2.7-8.3), respectively. Efficacy was observed in patients with AR ligand binding domain (LBD) WT or with AR LBD mutations. CONCLUSIONS: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with potentially higher benefit in chemotherapy-naïve patients. These data show BMS-986365's potential to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

3H-L-leucine transport by the promiscuous crustacean dipeptide-like cotransporter.

The crustacean intestine and hepatopancreas display a variety of solute transport mechanisms for transmembrane transfer of dietary contents from lumen to epithelial cytosol. An in vitro intestinal perfusion apparatus was used to characterize mucosal to serosoal (MS) and serosal to mucosal (SM) Zn(2+) -dependent (3)H-L-leucine transport by the intestine of the American lobster, Homarus americanus. Transmural 20 µM MS (3)H-L-leucine fluxes across lobster intestine were a hyperbolic function of luminal zinc concentration (1-50 µM) following Michaelis-Menten kinetics (K(m) = 2.67 ± 0.74 µM; J(max) = 19.56 ± 2.22 pmol/cm(2) ×min). Transmural 20 µM SM (3)H-L-leucine fluxes were not affected by serosal zinc, resulting in a highly significant stimulation of net amino acid transfer to the blood by luminal metal. MS fluxes of 20 µM (3)H-L-leucine were also hyperbolic functions of luminal [Cu(2+)], [Mn(2+)], [Na(+)], and [H(+)]. MS flux of (3)H-L-leucine was a sigmoidal function of luminal [L-leucine] and was stimulated by the addition of 20 µM luminal zinc at both pH 7.0 and 5.5. A greater enhanced amino acid transport occurred at the lower pH 5.5. MS flux of 20 µM (3)H-L-leucine in the presence of 20 µM zinc was significantly inhibited by addition of 100 µM luminal glycylsarcosine, and MS flux of 20 µM (3)H-glycylsarcosine was inhibited by 100 µM L-leucine in the presence of 20 µM zinc. Results suggest that (3)H-L-leucine and metals form a complex (e.g., Leu-Zn-Leu] that may functionally mimic dipeptides and use a dipeptide-like transporter during MS fluxes as suggested for fish and mammals.

Myosin VI is a processive motor with a large step size.

Myosin VI is a molecular motor involved in intracellular vesicle and organelle transport. To carry out its cellular functions myosin VI moves toward the pointed end of actin, backward in relation to all other characterized myosins. Myosin V, a motor that moves toward the barbed end of actin, is processive, undergoing multiple catalytic cycles and mechanical advances before it releases from actin. Here we show that myosin VI is also processive by using single molecule motility and optical trapping experiments. Remarkably, myosin VI takes much larger steps than expected, based on a simple lever-arm mechanism, for a myosin with only one light chain in the lever-arm domain. Unlike other characterized myosins, myosin VI stepping is highly irregular with a broad distribution of step sizes.

Use of percutaneous ethanol injection for treatment of bilateral hyperplastic thyroid nodules in cats.

OBJECTIVE: To determine the efficacy and safety of percutaneous ethanol injection (PEI) for the treatment of hyperthyroidism caused by bilateral hyperplastic thyroid nodules in cats. DESIGN; Prospective study. ANIMALS: 7 cats. PROCEDURE: Hyperthyroidism was diagnosed on the basis of clinical signs and increased serum total thyroxine (TT4) concentrations. The presence of 2 cervical thyroid nodules was confirmed by use of ultrasonography and technetium Tc 99m albumin thyroid scans. After the death of 1 cat that received PEI in both thyroid nodules at the same time, the protocol was changed to injecting ethanol into 1 nodule at a time, with at least 1 month between injections. Clinical signs, serum TT4 concentrations, serum ionized calcium concentrations, laryngeal function, findings on ultrasonographic examinations of the ventral cervical region, and results of thyroid scans were monitored. RESULTS: Serum TT4 concentrations transiently decreased in all 6 cats (into the reference range in 5 of 6 cats) within 4 days of the first staged ethanol injection. Each subsequent injection resulted in a transient decrease in serum TT4 concentration. The longest period of euthyroidism was 27 weeks. Adverse effects included Horner's syndrome, dysphonia, and laryngeal paralysis. One cat died of unrelated causes. One cat underwent bilateral thyroidectomy, 2 cats were treated with methimazole, and 2 cats that had increased serum TT4 concentrations were not treated further, because they remained clinically normal. CONCLUSIONS AND CLINICAL RELEVANCE: Percutaneous ethanol ablation of bilateral thyroid nodules as a treatment for cats with hyperthyroidism is not recommended. This treatment is not as efficacious as the medical and surgical treatments presently used.

Actin and light chain isoform dependence of myosin V kinetics.

Recent studies on myosin V report a number of kinetic differences that may be attributed to the different heavy chain (chicken vs mouse) and light chain (essential light chains vs calmodulin) isoforms used. Understanding the extent to which individual light chain isoforms contribute to the kinetic behavior of myosin V is of critical importance, since it is unclear which light chains are bound to myosin V in cells. In addition, all studies to date have used alpha-skeletal muscle actin, whereas myosin V is in nonmuscle cells expressing beta- and gamma-actin. Therefore, we characterized the actin and light chain dependence of single-headed myosin V kinetics. The maximum actin-activated steady-state ATPase rate (V(max)) of a myosin V construct consisting of the motor domain and first light chain binding domain is the same when either of two essential light chain isoforms or calmodulin is bound. However, with bound calmodulin, the K(ATPase) is significantly higher and there is a reduction in the rate and equilibrium constants for ATP hydrolysis, indicating that the essential light chain favors formation of the M. ADP.P(i) state. No kinetic parameters of myosin V are strongly influenced by the actin isoform. ADP release from the actin-myosin complex is the rate-limiting step in the ATPase cycle with all actin and light chain isoforms. We postulate that although there are significant light-chain-dependent alterations in the kinetics that could affect myosin V processivity in in vitro assays, these differences likely are minimized under physiological conditions.

The kinetic mechanism of myosin V.

Myosin V is an unconventional myosin proposed to be processive on actin filaments, analogous to kinesin on a microtubule [Mehta, A. D., et al. (1999) Nature (London) 400, 590-593]. To ascertain the unique properties of myosin V that permit processivity, we undertook a detailed kinetic analysis of the myosin V motor. We expressed a truncated, single-headed myosin V construct that bound a single light chain to study its innate kinetics, free from constraints imposed by other regions of the molecule. The data demonstrate that unlike any previously characterized myosin a single-headed myosin V spends most of its kinetic cycle (>70%) strongly bound to actin in the presence of ATP. This kinetic tuning is accomplished by increasing several of the rates preceding strong binding to actin and concomitantly prolonging the duration of the strongly bound state by slowing the rate of ADP release. The net result is a myosin unlike any previously characterized, in that ADP release is the rate-limiting step for the actin-activated ATPase cycle. Thus, because of a number of kinetic adaptations, myosin V is tuned for processive movement on actin and will be capable of transporting cargo at lower motor densities than any other characterized myosin.

Myosin VI is an actin-based motor that moves backwards.

Myosins and kinesins are molecular motors that hydrolyse ATP to track along actin filaments and microtubules, respectively. Although the kinesin family includes motors that move towards either the plus or minus ends of microtubules, all characterized myosin motors move towards the barbed (+) end of actin filaments. Crystal structures of myosin II (refs 3-6) have shown that small movements within the myosin motor core are transmitted through the 'converter domain' to a 'lever arm' consisting of a light-chain-binding helix and associated light chains. The lever arm further amplifies the motions of the converter domain into large directed movements. Here we report that myosin VI, an unconventional myosin, moves towards the pointed (-) end of actin. We visualized the myosin VI construct bound to actin using cryo-electron microscopy and image analysis, and found that an ADP-mediated conformational change in the domain distal to the motor, a structure likely to be the effective lever arm, is in the opposite direction to that observed for other myosins. Thus, it appears that myosin VI achieves reverse-direction movement by rotating its lever arm in the opposite direction to conventional myosin lever arm movement.

Diagnostic aspects and syndromal associations of short trachea with bronchial intubation.

Conditions with disproportionately short trachea, with a reduced number of tracheal cartilage rings and a high level of tracheal bifurcation, have been reported. We have seen accidental bronchial intubation in nine patients with short trachea. This risk can be reduced by recognition of conditions associated with short trachea, by awareness that methods for calculating endotracheal tube length from body length can overpredict tube length for patients with short trachea, and when feasible, by use of preintubation chest roentgenograms showing air bronchograms to establish the thoracic level of tracheal bifurcation. Twelve patients with short trachea, four with bronchial intubation, and six conditions not previously associated with short trachea, are reported. Three of the patients also had laryngeal hypoplasia.

Short trachea, a hazard in tracheal intubation of neonates and infants: syndromal associations.

Short trachea results from reduction in number of tracheal cartilage rings to 15 or fewer from normal mean of 17 rings in infants. In a review of radiologic and pathologic data, the thoracic vertebral level of tracheal bifurcation as seen in anteroposterior chest radiographs of infants with congenital malformations, cardiovascular anomalies, and skeletal dysplasias, was compared with numbers of tracheal cartilage rings demonstrated in postmortem specimens. Increased frequency of short trachea was seen in patients with DiGeorge anomaly (77%), skeletal dysplasias (55%), brevicollis (57%), diaplacental rubella (40%), and patients with congenital heart disease who did not have DiGeorge anomaly (36%, with range 25-83% for different types, the highest, 83%, being interrupted aortic arch). Preintubation high kilovoltage chest radiographs to establish the level of tracheal bifurcation in patients with increased risk of short trachea can be helpful in avoiding bronchial intubation and its complications. Postintubation chest films to assure the level of the endotracheal tube tip should be considered for such patients. Growth in length of the trachea with age is accomplished both by increase in size of tracheal cartilage rings and interring membranes, and by increase in ring number.

Effects of the respiratory cycle on cardiac output measurements: reproducibility of data enhanced by timing the thermodilution injections in dogs.

Cardiac output (Q) was measured with the thermodilution technique at 4 points during the respiratory cycle in dogs. Boluses of an ice-cold solution were injected at mid- and end-inspiration while the animals were on intermittent positive-pressure ventilation (IPPV) or after induction of positive end-expiratory pressure (PEEP), with and without induction of experimental respiratory failure. Values were mot constant at end-inspiration. During IPPV without respiratory failure, the standard error of 74 measurements at end-inspiration was 5.1% and of 74 measurements randomly selected was 9.8%. Continuous infusion resulted in similar fluctuations in Q (r = 0.92). Values obtained during experimental respiratory failure were not significantly different. The authors conclude that timing the bolus injections with the respiratory cycle enhances the reproducibility of Q values obtained with the thermodilution technique.

Perinatal foal mortality associated with a herpesvirus.

An outbreak of perinatal foal mortality associated with a herpesvirus is described. Twenty two foals either were still-born, or died soon after birth, or were weak and soon developed severe respiratory signs, or were normal at birth and developed respiratory symptoms 18 to 24 hours later. Elevated temperatures, heart and respiratory rates were constant features. The animals were severely leucopaenic, and showed an absolute neutropaenia. At autopsy the lungs were enlarged, and showed varying degrees of aeration and moderate to severe oedema and congestion. Histopathology showed an acute focal necrotising bronchiolitis with the presence of intranuclear eosinophilic inclusion bodies. Herpesvirus was recovered from 9 foals in cell culture and identified by electron microscopy.

Oestrogen-induced endometrial carcinoma in a patient with gonadal dysgenesis.

This case report describes the genesis of endometrial carcinoma after prolonged stilboestrol therapy in a patient with gonadal dysgenesis (Turner's syndrome). The varied histological appearance included the presence of cartilage-like material. A review of the literature reveals the need to treat these patients with combined oestrogen/progestogen preparations rather than with continuous unopposed oestrogens.

PIP: Gonadal dysgenesis was diagnosed in a 24-year-old patient presenting with primary amenorrhea. Because of her concern over poor breast development, .25 mg/day stilbestrol was prescribed. She was not seen again until 4 years later when she was admitted to hospital for heavy vaginal bleeding of uterine origin. Stilbestrol therapy was stopped. The uterus was enlarged, and curettings showed striking changes in the epithelium and the presence of cartilagelike material. Hysterectomy was performed a month later, and histological examination showed changes similar to those seen earlier but no penetration of the myometrium. The histological features were extremely variable, but the lesion was put in the adenosquamous category. The presence of cartilage in this type of lesion has not been previously reported. The 4-year stilbestrol treatment is shorter than the 5-year-plus average treatment duration reported in other cases of estrogen-induced malignant change. Although it may be suspected that the longer the duration of estrogen treatment, the more likely the chance of myometrial invasion and spread beyond the uterus, no fatal case has been found of such metastases. However, it is now agreed that cyclic estrogen-progestogen therapy for gonadal dysgenesis is safer.