Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2).

Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 - K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.

Molecular basis of ClC-6 function and its impairment in human disease.

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

A discrete choice experiment on oral and injection treatment preferences among moderate-to-severe psoriasis patients in Japan.

Long-term psoriasis (PsO) management remains challenging. With growing variation in treatment efficacy, cost, and modes of administration, patient preferences for different treatment characteristics are not well understood. A discrete choice experiment (DCE), informed by qualitative patient interviews, was conducted to assess patient preferences for different attributes of PsO treatments; 222 adult patients with moderate-to-severe PsO receiving systemic therapy participated in the DCE web survey. Better long-term efficacy and lower cost were preferred (preference weights p < 0.05). Long-term efficacy had the highest relative importance (RI) and mode of administration was as important as the outcome attributes (efficacy and safety). Patients also preferred oral to injectable administration. In subgroup analyses by disease severity, residence, psoriatic arthritis as a comorbidity, and gender, the trends for each subgroup were the same as the overall population although the extent of RI for administration mode varied. Mode of administration was more important for patients with moderate versus severe disease, or rural versus urban residence. This DCE utilized attributes related to both oral and injectable treatment as well as a broad study population of systemic treatment users. Preferences were further stratified by patient characteristics to explore trends in different subgroups. Understanding the RI of treatment attributes and the attribute trade-offs acceptable to patients helps inform moderate-to-severe PsO systemic treatments decisions.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BACKGROUND: Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. METHODS: This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. RESULTS: There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44-64] vs 42 years [IQR 35-50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5-8] vs 5 [IQR 4-6]), more co-medications (median 6 [IQR 4-11] vs 3 [IQR 2-7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). CONCLUSION: The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

MEdical Database AnaLysIS of Japanese multiple myeloma patienTs with apheresis #2 (MEDALIST-2): the impact of plerixafor use on costs and healthcare resources during mobilization and stem cell transplantation.

Treatment for multiple myeloma (MM) can involve apheresis to mobilize hematopoietic stem cells for later autologous stem cell transplantation (ASCT), which can become costly over time. This retrospective claims database study examined healthcare resource use and medical costs associated with plerixafor, a selective CXCR4 inhibitor that mobilizes hematopoietic stem cells and minimizes apheresis times. Medical data were sampled from Japanese MM patients between April 2017 and September 2019, after the Japanese launch of plerixafor. The study population (190 plerixafor users and 180 non-users) was identified from the Medical Data Vision database, and further stratified into those using granulocyte-colony stimulating factor in monotherapy or in combination with cyclophosphamide to trigger apheresis. A descriptive comparison of patient characteristics, healthcare resource use, and medical costs across the mobilization and ASCT phases indicated plerixafor is associated with higher average total medical costs. However, plerixafor-treated patients received fewer concomitant medications and spent less time in apheresis than non-users. A comparison of non-users with a similar analysis conducted pre-plerixafor launch (2013-2017) showed general improvements to treatment independent of plerixafor. The results of this research can inform guidelines for the role of plerixafor in balancing cost-effectiveness and drug efficacy in MM treatment.

Cost drivers associated with diffuse large B-cell lymphoma (DLBCL) in Japan: A structural equation model (SEM) analysis.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin's lymphoma of increasing prevalence in Japan. However, patients with relapsed or refractory disease to first line treatment (rrDLBCL) have been found to shoulder greater economic burden and have poor survival with subsequent lines of therapy. The relative impact of individual patient attributes on total medical cost among patients with rrDLBCL receiving second or third line (2L/3L) therapy was assessed. Structural equation modelling was used to identify potential cost drivers of total medical costs incurred by treatment and procedures in a Japanese retrospective claims database. From the database, rrDLBCL patients on 2L or 3L of treatment were grouped into respective cohorts. The mean [median] (SD) total medical cost of care for the 2L cohort was 73,296.40 [58,223.11] (58,409.79) US dollars (USD) and 75,238.35 [60,477.31] (59,583.66) USD for the 3L cohort. The largest total effect on medical cost in both cohorts was length of hospital stay (LOS) (ß: 0.750 [95%CI: 0.728, 0.772] vs ß: 0.762 [95%CI: 0.729, 0.794]). Length of hospital stay and potential heart disease complications due to line of treatment were the primary drivers of total cost for patients who had received at least 2L or 3L therapy for rrDLBCL.

Medical Costs Associated with Insomnia Treatment with Suvorexant Monotherapy in Japan: Results from a Retrospective Cohort Study Using a Large-Scale Claims Database.

BACKGROUND: The association of insomnia treatment with medical costs is not well characterized in Japan, despite the high economic burden of insomnia. OBJECTIVE: The aim of this study was to investigate the impact of suvorexant, the first dual orexin receptor antagonist, on direct medical costs in insomnia patients. PATIENTS AND METHODS: This retrospective cohort study, conducted using a large-scale claims database, included Japanese patients with diagnosed insomnia receiving suvorexant who were treatment naïve or treatment switchers (pre-treated with a different hypnotic and switched to suvorexant). Total medical costs were estimated for 1 year before and after suvorexant initiation; p-values were calculated for the difference in costs. RESULTS: Of the 1730 patients included, 1116 were treatment naïve and 614 were treatment switchers. Switching to suvorexant did not change the total treatment cost (US$4693-US$4692; p = 0.9964). Although treatment-naïve patients on average incurred US$3259 after suvorexant initiation, much of the additional cost was attributed to drugs other than hypnotics in the outpatient setting (US$332; p < 0.0001). While ~ 10% of the additional medical costs in the outpatient setting were attributable to hypnotics in both groups (treatment naïve: US$106, p < 0.0001; treatment switchers: US$115, p < 0.0001), no difference was observed in the inpatient setting. CONCLUSION: Suvorexant as an initial insomnia treatment was associated with higher total medical costs, given the additional burden of initiating treatment and monitoring costs associated with a new insomnia diagnosis. However, despite a switch from another hypnotic, suvorexant did not increase the incremental economic burden. The hypnotic cost remained proportionately low, demonstrating that suvorexant initiation did not raise the cost of insomnia treatment.

Systematic review of survival outcomes for relapsed or refractory adult T-cell leukemia-lymphoma.

INTRODUCTION: Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell lymphoproliferative neoplasm caused by human T-cell leukemia virus type-1 infection. There is no standard treatment for relapsed or refractory (r/r) ATL, and clinical outcomes are poor. This systematic review examined the survival outcomes for r/r ATL treated with various systemic therapies. METHODS: EMBASE and PubMed were searched for studies on r/r ATL, published between January 2010 and January 2020. The main outcome of interest was overall survival (OS). Median OS and an exploratory 30% OS time were assessed based on published data and Kaplan-Meier curves. RESULTS: There were 21 unique treatment subgroups (from 14 studies), that met the eligibility criteria. Nine subgroups were mogamulizumab treatment, two were mogamulizumab prior to allogenic hematopoietic stem cell transplantation (allo-HSCT), five were allo-HSCT, and five were other chemotherapy. Respectively, the median OS and 30% OS varied considerably in range for mogamulizumab treatment (2.2-17.6 months and 8.7-27.1 months), allo-HSCT (3.8-6.2 months and 7.5-19.8 months), and other chemotherapy arms (4.1-20.3 months and 7.1-17.0 months). CONCLUSION: Mogamulizumab was the most frequently studied treatment regimen and can potentially provide longer survival compared with chemotherapy alone. Future comparisons with synthetic or historical control arms may enable clearer insights into treatment efficacy.

Economic burden in treated Japanese patients with relapsed/refractory large B-cell lymphoma.

Aim: To understand the economic burden of relapsed and refractory large B-cell lymphoma patients in Japan treated with salvage chemotherapy. Patients & methods: Patients who received systemic therapy after first-line treatment were analyzed to assess its associated cost and resource use using a retrospective claims database. The impact of COVID-19 was assessed separately. Results & conclusion: This study identified 2927 and 1085 patients in the second- (2L) and third-line (3L) cohorts. The median ages for the 2L and 3L cohorts were 71 and 70 years, respectively, with Charlson Comorbidity Score of 3. A majority of the patients had limited stem cell transplant due to advanced age. Median lengths of inpatient stay for the 2L and 3L cohorts were 118 and 116 days, respectively. The majority of costs were attributed to inpatient costs, and limited COVID-19 impact was observed in this study.

Comparative effectiveness study of chemotherapy in follicular lymphoma patients in the rituximab era: a Japanese claims database study.

Aim: To evaluate comparative effectiveness of rituximub (R)-based versus non-R-based therapies for follicular lymphoma patients in Japan, where limited studies have been reported. Materials & methods: Patients who received R-based index regimens were propensity score matched to those who did not receive R, based on patient baseline attributes and clinical characteristics using Japanese retrospective claims database to assess clinical and economic outcomes. Results & conclusion: A total of 1947 patients remained in the overall follicular lymphoma cohorts: 1294 receiving an R-based and 653 a non-R-based regimen. Patients on R-based therapy underwent fewer hospitalizations and had a shorter length of stay, but had higher costs during the first year of intensive R-based therapy. Improved clinical outcomes were associated with patients who were younger, female and chose R-based regimens in first index line.

Atomic structure of human TOM core complex.

The translocase of the outer mitochondrial membrane (TOM) complex is the main entry gate for mitochondrial precursor proteins synthesized on cytosolic ribosomes. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the dimeric human TOM core complex (TOM-CC). Two Tom40 ß-barrel proteins, connected by two Tom22 receptor subunits and one phospholipid, form the protein-conducting channels. The small Tom proteins Tom5, Tom6, and Tom7 surround the channel and have notable configurations. The distinct electrostatic features of the complex, including the pronounced negative interior and the positive regions at the periphery and center of the dimer on the intermembrane space (IMS) side, provide insight into the preprotein translocation mechanism. Further, two dimeric TOM complexes may associate to form tetramer in the shape of a parallelogram, offering a potential explanation into the unusual structural features of Tom subunits and a new perspective of viewing the import of mitochondrial proteins.

Nationwide claims database analysis of treatment patterns, costs and survival of Japanese patients with diffuse large B-cell lymphoma.

Limited data are available regarding treatment patterns, healthcare resource utilization (HCRU), treatment costs and clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL) in Japan. This retrospective database study analyzed the Medical Data Vision database for DLBCL patients who received treatment during the identification period from October 1 2008 to December 31 2017. Among 6,965 eligible DLBCL patients, 5,541 patients (79.6%) received first-line (1L) rituximab (R)-based therapy, and then were gradually switched to chemotherapy without R in subsequent lines of therapy. In each treatment regimen, 1L treatment cost was the highest among all lines of therapy. The major cost drivers i.e. total direct medical costs until death or censoring across all regimens and lines of therapy were from the 1L regimen and inpatient costs. During the follow-up period, DLBCL patients who received a 1L R-CHOP regimen achieved the highest survival rate and longest time-to-next-treatment, with a relatively low mean treatment cost due to lower inpatient healthcare resource utilization and fewer lines of therapy compared to other 1L regimens. Our retrospective analysis of clinical practices in Japanese DLBCL patients demonstrated that 1L treatment and inpatient costs were major cost contributors and that the use of 1L R-CHOP was associated with better clinical outcomes at a relatively low mean treatment cost.

Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.

OBJECTIVE: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. RESULTS: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. CONCLUSION: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.

Comparative effectiveness of first-line nab-paclitaxel versus paclitaxel monotherapy in triple-negative breast cancer.

Aim: This observational study evaluated the effectiveness of nab-paclitaxel versus paclitaxel monotherapy as first-line (1L) treatment for metastatic triple-negative breast cancer (mTNBC). Materials & methods: 200 patients from the US Flatiron Health electronic health record-derived database (mTNBC diagnosis, January 2011-October 2016) who received 1L nab-paclitaxel (n = 105) or paclitaxel (n = 95) monotherapy were included. Overall survival and time to next treatment were evaluated. Results: The adjusted overall survival hazard ratio was 0.98 (95% CI: 0.67-1.44), indicating a similar risk of death between groups. Adjusted time to next treatment hazard ratio was 0.89 (95% confidence interval: 0.62-1.29). Conclusion: Nab-paclitaxel and paclitaxel monotherapy showed similar efficacy, suggesting their interchangeability as 1L treatments for mTNBC.

Cryo-EM structure of the mammalian ATP synthase tetramer bound with inhibitory protein IF1.

The mitochondrial adenosine triphosphate (ATP) synthase produces most of the ATP required by mammalian cells. We isolated porcine tetrameric ATP synthase and solved its structure at 6.2-angstrom resolution using a single-particle cryo-electron microscopy method. Two classical V-shaped ATP synthase dimers lie antiparallel to each other to form an H-shaped ATP synthase tetramer, as viewed from the matrix. ATP synthase inhibitory factor subunit 1 (IF1) is a well-known in vivo inhibitor of mammalian ATP synthase at low pH. Two IF1 dimers link two ATP synthase dimers, which is consistent with the ATP synthase tetramer adopting an inhibited state. Within the tetramer, we refined structures of intact ATP synthase in two different rotational conformations at 3.34- and 3.45-Å resolution.

Uncovering burden disparity: A comparative analysis of the impact of moderate-to-severe psoriasis and hidradenitis suppurativa.

BACKGROUND: Psoriasis and hidradenitis suppurativa (HS) exhibit distinct clinical features, but no studies have directly compared the health-related quality of life (HRQoL) in patients with moderate-to-severe manifestations of these conditions. OBJECTIVE: To determine which disease is associated with more severe HRQoL impairment. METHODS: Weighted averages of each of the following baseline HRQoL measures were determined and compared between HS and psoriasis populations from 5 clinical trials: Visual Analog Scale (VAS) for pain, Total Work Productivity Impairment, Dermatology Life Quality Index; EuroQOL 5D VAS, and Short Form-36 Health Survey. RESULTS: Compared with patients with psoriasis, patients with HS reported higher scores for VAS-pain (54.3 vs 36.1 [P < .0001]), Dermatology Life Quality Index (15.3 vs 11.3 [P < .0001]), EuroQOL 5D VAS (58.8 vs 50.8 [P < .0002]), and Total Work Productivity Impairment (35.4 vs 18.2). Patients with HS had lower Short Form-36 Health Survey scores than did patients with psoriasis (physical, 39.6 vs 49.0; mental, 41.5 vs 47.5 [both P < .0001]). LIMITATIONS: This analysis was performed using published summary data rather than patient-level data, and weighted pooled averages were compared. CONCLUSIONS: Patients with HS have a higher HRQoL burden than patients with psoriasis. This study clearly documents the needs of patients with HS and the potential impact of medical, scientific, and societal consensus for the development of more effective HS treatments.