Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study

INTRODUCTION: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness.METHODS: Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages).RESULTS: Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%&lt;80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up.CONCLUSION: The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials.CLINICAL TRIAL NUMBER: NCT04478981.</p

Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study

INTRODUCTION: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness.METHODS: Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages).RESULTS: Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%&lt;80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up.CONCLUSION: The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials.CLINICAL TRIAL NUMBER: NCT04478981.</p

Randomised trials comparing different healthcare settings : an exploratory review of the impact of pre-trial preferences on participation, and discussion of other methodological challenges

BACKGROUND: We recently published a systematic review of different healthcare settings (such as outpatient, community or home) for administering intravenous chemotherapy, and concluded that performing conventionally designed randomised trials was difficult. The main problems were achieving adequate trial accrual rates and recruiting a study population which adequately represented the target population of interest. These issues stemmed from the fact that potential participants may have had pre-trial perceptions about the trial settings they may be allocated; such preferences will sometimes be strong enough for patients to decline an invitation to participate in a trial. A patient preference trial design (in which patients can choose, or be randomised to, an intervention) may have obviated these recruitment issues, although none of the trials used such a design. METHODS: In order to gain a better understanding of the broader prevalence and extent of these preference issues (and any other methodological challenges), we undertook an exploratory review of settings trials in any area of healthcare treatment research. We searched The Cochrane Library and Google Scholar and used snowballing methods to identify trials comparing different healthcare settings. RESULTS: Trial accrual was affected by patient preferences for a setting in 15 of the 16 identified studies; birth setting trials were the most markedly affected, with between 68 % and 85 % of eligible women declining to participate specifically because of preference for a particular healthcare setting. Recruitment into substance abuse and chemotherapy setting studies was also notably affected by preferences. Only four trials used a preference design: the proportion of eligible patients choosing to participate via a preference group ranged from between 33 % and 67 %. CONCLUSIONS: In trials of healthcare settings, accrual may be seriously affected by patient preferences. The use of trial designs which incorporate a preference component should therefore strongly be considered. When designing such trials, investigators should consider settings to be complex interventions, which are likely to have linked components which may be difficult to control for. Careful thought is also needed regarding the choice of comparator settings and the most appropriate outcome measures to be used

The photochemistry of N-p-toluenesulfonyl peptides: the peptide bond as an electron donor

The scope of photobiological processes that involve absorbers within a protein matrix may be limited by the vulnerability of the peptide group to attack by highly reactive redox centers consequent upon electronic excitation. We have explored the nature of this vulnerability by undertaking comprehensive product analyses of aqueous photolysates of 12 N-p-toluene-sulfonyl peptides with systematically selected structures. The results indicate that degradation includes a major pathway that is initiated by intramolecular electron transfer in which the peptide bond serves as electron donor, and the data support the likelihood of a relay process in dipeptide derivatives

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented

Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Summary: The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteom