Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT.

WHAT IS THIS SUMMARY ABOUT?: This summary describes a publication about a study called SPRINT. The SPRINT study included 50 children with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) that could not be removed with surgery. PNs are tumors that grow along nerves and can cause various problems for children, such as pain, changes to appearance, and muscle weakness. In SPRINT, the study team wanted to learn whether a medication called selumetinib was able to shrink the PN caused by NF1 (also known as NF1-related PN), and if shrinking PNs helped relieve children of the problems caused by it. To assess how selumetinib might help, children had scans to measure the size of their PN, completed questionnaires, and had a variety of other tests done by their doctor. Their caregivers also completed questionnaires about their child. The children took selumetinib capsules twice a day on an empty stomach. WHAT WERE THE RESULTS?: The results showed that selumetinib was able to shrink the PN for most children (68%). The results also showed that the problems caused by the children's PNs mostly improved while on selumetinib treatment. SPRINT also showed that the side effects of selumetinib were mainly mild and could be managed by doctors. WHAT DO THE RESULTS MEAN?: Before SPRINT, there were not many treatment options for children with NF1 and PN as there were no medications that had been shown to shrink PN, and surgery was not always possible. SPRINT showed that this medication shrinks most PNs and could help children with NF1 and PN. In April 2020, selumetinib was approved by the US Food and Drug Administration (FDA) because of the results of SPRINT. Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. Clinical Trial Registration: NCT01362803 (SPRINT) (ClinicalTrials.gov).

Effective Treatment of Chronic Mastectomy Pain with Intercostal Sensory Neurectomy.

SUMMARY: Chronic postmastectomy pain affects up to 40 percent of patients and leads to diminished quality of life and increased risk of opioid dependence. The cause of this pain is incompletely understood; however, one hypothesis is that direct injury to cutaneous intercostal nerves at the time of mastectomy and/or reconstruction leads to chronic pain. As a result, proximal neurectomy of the involved sensory nerve(s) has been suggested to be effective for these patients. The purpose of this study was to determine whether chronic pain in postmastectomy patients can be diagnosed reliably in an office setting and pain reduced by intercostal sensory neurectomy. The authors performed a retrospective review of seven patients with a history of breast surgery and chronic pain who underwent intercostal neurectomy combined with muscle or dermal wrapping of the proximal end of the resected nerve. All patients were diagnosed by history and physical examination, and suspected nerves were further identified with local anesthetic nerve blocks. An average of 3.14 neurectomies were performed per patient (range, one to six). There was a significant reduction in visual analogue scale pain scores following surgery, from 9 preoperatively to 1 postoperatively (p = 0.02). Eighty-six percent of patients were pain-free or "considerably improved" at their latest follow-up appointment (average, 6.14 months). It is concluded that intercostal sensory nerve injury at the time of mastectomy and/or reconstruction can lead to chronic mastectomy pain, which can be easily diagnosed and effectively treated with intercostal neurectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Dermatosensory Peripheral Nerve Interfaces: Prevention of Pain Recurrence Following Sensory Neurectomy.

Chronic pain is a significant health care problem. Many patients' pain can be linked to a neuropathic origin, diagnosed with a thorough history and physical examination, and confirmed with a diagnostic nerve block. There are new procedures designed to address neuropathic pain from symptomatic neuromas by providing physiologic targets for regenerating axons following neurectomy. Dermal wrapping of the end of a sensory nerve following transection, a technique called dermatosensory peripheral nerve interface, may provide an optimal environment to prevent neuroma pain and reduce chronic neuropathic pain.

Association of Clinical Complications of Chemotherapy and Patient-Reported Outcomes After Immediate Breast Reconstruction.

Importance: Women undergoing immediate breast reconstruction often require chemotherapy. The effects of chemotherapy on reconstruction are not well described. Objective: To evaluate the association of neoadjuvant and adjuvant chemotherapy with complications and patient-reported outcomes (PROs) in immediate reconstruction. Design, Setting, and Participants: The Mastectomy Reconstruction Outcomes Consortium Study is a cohort study that prospectively assessed PROs and retrospectively evaluated complications in patients undergoing immediate implant-based or autologous reconstruction at 11 centers from January 1, 2012, to December 31, 2017. Women 18 years or older undergoing immediate reconstruction after mastectomy with 2 years of follow-up were included. Patients were excluded if they had prophylactic mastectomy; delayed reconstruction; mixed-timing reconstruction; mixed reconstruction; a latissimus dorsi, superior gluteal artery perforator, or inferior gluteal artery perforator flap; or both neoadjuvant and adjuvant chemotherapy. Data were analyzed from May 1 to June 30, 2018. Main Outcomes and Measures: Complications and PROs (satisfaction with breast and physical, psychosocial, and sexual well-being) using the BREAST-Q questionnaire, a validated, condition-specific PRO measure. Baseline patient characteristics were collected. Results: A total of 1881 women were included in the analysis (mean [SD] age, 49.9 [9.9] years). Of these, 1373 (73.0%) underwent implant-based procedures; 508 (27.0%), autologous reconstruction; 200 (10.6%), neoadjuvant chemotherapy; 668 (35.5%), adjuvant chemotherapy; and 1013 (53.9%), no chemotherapy. Patients without chemotherapy were significantly older (mean [SD] age, 51.6 [9.4] years; P < .001), and patients with chemotherapy were more likely to have received radiotherapy (108 of 200 [54.0%] for neoadjuvant chemotherapy and 321 of 668 [48.1%] for adjuvant chemotherapy; P < .001). Among the cohort undergoing implant-based reconstruction, the rates of any complication were significantly different, with higher rates seen for adjuvant (153 of 490 [31.2%]) and neoadjuvant (44 of 153 [28.8%]) chemotherapy compared with no chemotherapy (176 of 730 [24.1%]; P = .02). On multivariable analysis, these differences were not statistically significant. For autologous reconstruction, no significant differences in complications were observed. Controlling for clinical covariates, no significant differences were seen across chemotherapy groups for the BREAST-Q subscales except for sexual well-being in the implant cohort, in which adjuvant chemotherapy had significantly lower scores (ß, -4.97 [95% CI, -8.68 to -1.27]; P = .009). Conclusions and Relevance: In this cohort study, neither neoadjuvant nor adjuvant chemotherapy was associated with the likelihood of complications in patients undergoing implant-based or autologous reconstruction, and chemotherapy was not associated with patient satisfaction with reconstruction or psychosocial well-being. This information can help patients and clinicians make informed decisions about breast reconstruction in the setting of chemotherapy.

Preterm Stress Behaviors, Autonomic Indices, and Maternal Perceptions of Infant Colic.

BACKGROUND: While biological and behavioral stress response systems are intact in early gestation, preterm infants' behaviors are often more subtle and difficult to interpret compared with full-term infants. They are also more vulnerable for regulatory issues (ie, colic) that are known to impact caregiver-infant interactions. Biobehavioral measures such as behavioral responsivity and heart rate variability (HRV), particularly cardiac vagal tone, may help elucidate preterm infants' stress/regulatory systems. PURPOSE: To test the hypotheses that preterm infants' consoling behaviors and high-frequency (HF) HRV in the first week of life are significantly associated and they are inverse correlates of future colic risk. METHODS/SEARCH STRATEGY: Thirty preterm (mean ± SE = 32.7 ± 0.3 weeks postmenstrual age [PMA]) infants underwent direct NIDCAP (Newborn Individualized Development and Assessment Program) observation during routine care and had HRV measurements during their first week postbirth. Sixty-three percent of mothers completed the Infant Colic Scale at 6 to 8 weeks adjusted postnatal age. Nonparametric tests were used to determine associations among behaviors, HRV, and maternal perceptions of infant colic. FINDINGS/RESULTS: Self-consoling behaviors were positively associated with HF-HRV (vagal tone). In addition, stress behaviors were positively associated with low-frequency/high-frequency HRV (sympathetic dominance). Infants who displayed more stress behaviors also demonstrated more self-consoling behaviors. No significant associations were found with colic. IMPLICATIONS FOR PRACTICE: HF-HRV provides information on the infant's capacity to modulate stress and is a useful, noninvasive measure when behaviors are more difficult to discern. IMPLICATIONS FOR RESEARCH: Further study in a larger sample is needed to determine whether behavioral stress measures and HF-HRV may be useful to determine colic risk.

Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols. METHODS: 7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice. RESULTS: In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3ß,5α-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3ß,5α-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups. CONCLUSIONS: Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.

Docking of cytochrome c6 and plastocyanin to the aa3-type cytochrome c oxidase in the cyanobacterium Phormidium laminosum.

The interactions between redox proteins are transient in nature. Therefore, very few crystal structures are available for the complexes formed between these proteins. Computational docking simulations thus provide a useful alternative method for studying the interactions between electron transfer proteins. In this paper, we have studied the interactions between the aa(3)-type cytochrome c oxidase of the cyanobacterium Phormidium laminosum and its redox partners plastocyanin and cytochrome c(6) using a combination of comparative modelling techniques and docking simulations. Rigid-body docking orientations were scored with a combined energy function that accounts for electrostatics and desolvation. These simulations have identified two plausible docking sites, one of which appears to be unique to the binding of plastocyanin to the oxidase. This unique binding site may be due to the presence of a long loop region in the subunit II of cyanobacterial oxidases. Control simulations were performed with the ba(3)-type cytochrome c oxidase and its redox partner cytochrome c(552) from Thermus thermophilus. The docking between cytochrome c oxidase and its redox partners plastocyanin and cytochrome c(6) is dominated by hydrophobic residues, a feature already observed from kinetic and structural studies in other complexes of P. laminosum (e.g. plastocyanin or cytochrome c(6) with cytochrome f and photosystem I).

Role of charges on cytochrome f from the cyanobacterium Phormidium laminosum in its interaction with plastocyanin.

The role of charge on the surface of cytochrome f from the cyanobacterium Phormidium laminosum in the reaction with plastocyanin was investigated in vitro using site-directed mutagenesis. Charge was neutralized at five acidic residues individually and introduced at a residue close to the interface between the two proteins. The effects on the kinetics of the reaction were measured using stopped-flow spectrophotometry, and the midpoint potentials of the mutant proteins were determined. The dependence of the bimolecular rate constant of reaction, k(2), on ionic strength was determined for the reactions of the cytochrome f mutants with wild-type and mutant forms of plastocyanin. Double mutant cycle analysis was carried out to probe for the presence of specific electrostatic interactions. The effects of mutations on Cyt f were smaller than those seen previously for mutants of plastocyanin [Schlarb-Ridley, B. G. et al. (2002) Biochemistry 41, 3279-3285]. One specific short-range interaction between charged residues of wild-type plastocyanin (Arg93) and wild-type cytochrome f (Asp63) was identified. The kinetic evidence from this study and that of Schlarb-Ridley et al., 2002, appears to conflict with the NMR structure of the P. laminosum complex, which suggests the absence of electrostatic interactions in the final complex [Crowley, P. et al. (2001) J. Am. Chem. Soc. 123, 10444-10453]. The most likely explanation of the apparent paradox is that the overall rate is diffusion controlled and that electrostatics specifically influence the encounter complex and not the reaction complex.

The SWIB and the MDM2 domains are homologous and share a common fold.

Using a novel algorithm for protein sequence/structure analysis, we propose a probable homology between the SWIB domain (the conserved domain of the 60 kda subunit of the SWIB complex involved in chromatin remodelling) and the p53-binding domain of the MDM2 oncoprotein. The homology suggests that the SWIB domain would adopt a structure similar to that of the MDM2 domain and that these two families of proteins may share a similar functional mechanism.