Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Post-operative tension spinal subdural extra-arachnoid hygroma of the lumbar spine: case series, literature review, and recommendations for clinical management.

OBJECTIVE: Case series presentation and literature review of patient group suffering from symptomatic tension subdural extra-arachnoid hygroma following decompressive surgery for degenerative lumbar stenosis or disc disease. The purpose was to better understand this rare post-operative complication with a pathognomic radiological sign to help recommend optimal strategies for clinical management. METHODS: Retrospective case series comprising seven cases from one tertiary Neurosurgical centre spanning a 10-year period from 2011 to 2021. Patients included were those known to have undergone a spinal procedure and subsequently to have developed a symptomatic spinal subdural extra-arachnoid hygroma (SSEH). A literature review was conducted using PubMed, MEDLINE and EMBASE (keywords 'subdural hygroma', 'lumbar CSF hygroma', 'extra arachnoid hygroma', 'extra-arachnoid CSF collection', 'CSF tension hygroma', 'lumbar extra arachnoid hygroma', 'lumbar spinal hygroma', 'post-operating spinal hygroma', 'post-operative spinal CSF collection') and through reading references cited in relevant articles. Articles involving post-operative SSEH following lumbar spinal surgery were included. RESULTS: Rare complication with only five other cases in the literature. Dural breach described intra-operatively in only 5 of 12 total cases from our series and the literature. 5 patients in our series were managed surgically with 2 being managed conservatively. All patients in our series improved symptomatically and radiologically following surgical or conservative management. CONCLUSIONS: This is a rare post-lumbar surgery complication that can cause rapidly deteriorating lower limb and sphincteric function. Surgical management with wide durotomy and arachnoid marsupialisation can lead to reversal of neurological deterioration and excellent clinical results. A delayed presentation with pseudomeningocele formation may be managed conservatively if neurology is stable or improving. It is a condition that it is important for the clinician to recognise in order to instigate appropriate management in a time-dependent fashion.

Perioperative Blood Loss after Preoperative Prostatic Artery Embolization in Patients Undergoing Simple Prostatectomy: A Propensity Score‒Matched Study.

PURPOSE: To assess perioperative blood loss following prostatic artery embolization (PAE) before surgery in patients undergoing simple prostatectomy. METHODS: A retrospective chart review was used to identify 63 patients (mean age, 65.3 ± 8.0 years) with prostatic hypertrophy and severe lower urinary tract symptoms who underwent prostatectomy from September 2014 to December 2019, 18 (28.5%) of whom underwent PAE before surgery. Demographic data, pertinent laboratory results, procedural or operative information, hospital course details, and pathology reports were obtained. A 2:1 propensity score‒matching analysis was performed to compare intraoperative blood loss in patients who underwent prostatectomy alone with intraoperative blood loss in those who first underwent bilateral PAE before surgery. RESULTS: Sixteen (89%) of the 18 patients underwent bilateral PAE before surgery. Thirty-two patients who underwent prostatectomy without embolization before surgery were selected for the 2:1 propensity score‒matched analysis based on age, race, surgery type, prostate gland size, and comorbidities. The mean estimated blood loss (EBL) for prostatectomy alone was 545 ± 380 mL (mean ± standard deviation). There was a statistically significant reduction in the EBL for patients who underwent bilateral PAE (303 ± 227 mL, P < .01). The operative time was also significantly decreased for patients who underwent PAE before surgery (P < .05). For patients who underwent PAE, there were no complications related to the procedure. CONCLUSIONS: Bilateral PAE before surgery appears to be safe and may be effective in reducing perioperative bleeding and operative time.

Evaluation of Pharmacist Impact Within an Interdisciplinary Inpatient Heart Failure Consult Service.

Background: Heart failure (HF) is highly prevalent in the Veterans Affairs (VA) health care system and the leading cause of hospital discharges in the VA. Despite guideline-specific recommendations of drug therapy, many patients are not on optimal medication regimens. Objective: To examine and quantify pharmacist impact in an interdisciplinary HF consult (IC) service on increasing use of guideline-directed medical therapy (GDMT). The 30-day readmission rates before and after the implementation of an IC service are reported. Methods: This was a single-center retrospective analysis of veterans admitted with a HF diagnosis between August 2008 and August 2015 in 2 distinctive cohorts: pre-IC (August 2008 to November 2011) and IC (November 2011 to August 2015). Results: Four-hundred patients were included, with 200 in each cohort. All-cause readmissions at 30 days were not different between pre-IC and IC groups: 33.5% versus 28.5%, respectively. Secondary outcomes of HF readmission and 1-year mortality were not different between groups. Significant increases in medication use rates were observed from admission to discharge in both cohorts; however, greater increases were observed in the IC group in which the pharmacist role was clearly defined in recommending GDMT optimization, especially in patients with HF with reduced ejection fraction. Conclusion and Relevance: Although the implementation of an IC service did not significantly change 30-day readmission rates, increases in GDMT use are evident with increased pharmacist involvement. Longer-term outcomes associated with this intervention warrant future investigation.

Zebras in Foreskin Dermatopathology: A Review.

OBJECTIVES: The aim of the study was to review uncommon foreskin dermatopathology conditions clinically and pathologically. METHODS: A database search of PubMed and Google Scholar were extracted between March 1, 2009, and March 1, 2019, using the search terms "foreskin," "prepuce," "penis," "pathology," "dermatology," and "rare." The search was limited to "humans" and "dermatopathology." Full article texts were reviewed. Reference lists were screened for additional articles. Patient details (diagnosis, dermatopathology, treatment, and follow-up if available) were extracted. We excluded articles written in the non-English language, unusual variants of common conditions, and cases of common dermatologic conditions. RESULTS: A list of 369 articles was identified and another screening identified 30 articles for rare foreskin pathologies. Those are divided into categories based on the following etiologies: (a) benign, including congenital (e.g., aposthia), infectious (graft versus host disease and histoplasma), autoimmune (Crohn's disease and pyoderma gangrenosum), and benign neoplasms (neurofibroma, apocrine hidrocystoma, verruciform xanthoma, porokeratosis, penile cutaneous horn, localized amyloidosis) and (b) malignancies, including primary (myeloid sarcoma, basal cell carcinoma, Kaposi's sarcoma, mucosal-associated lymphoid tissue lymphoma), and metastasis. CONCLUSIONS: We reviewed and discussed unusual benign and malignant dermatopathology conditions that can affect the foreskin.

Enzyme-containing spin membranes for rapid digestion and characterization of single proteins.

Proteolytic digestion is an important step in characterizing protein sequences and post-translational modifications (PTMs) using mass spectrometry (MS). This study uses pepsin- or trypsin-containing spin membranes for rapid digestion of single proteins or simple protein mixtures prior to ultrahigh-resolution Orbitrap MS analysis. Centrifugation of 100 µL of pretreated protein solutions through the functionalized membranes requires less than 1 min and conveniently digests proteins into large peptides that aid in confirming specific protein sequence variations and PTMs. Peptic and tryptic peptides from spin digestion of apomyoglobin and four commercial monoclonal antibodies (mAbs) typically cover 100% of the protein sequences in direct infusion MS analysis. Increasing the spin rate leads to a higher fraction of large peptic peptides for apomyoglobin, and MS analysis of peptic and tryptic peptides reveals mAb PTMs such as N-terminal pyroglutamate formation, C-terminal lysine clipping and glycosylation. Relative to overnight in-solution digestion of mAbs, spin digestion yields higher sequence coverages. Spin-membrane digestion followed by infusion MS readily differentiates a mAb to the Ebola virus from a related antibody that differs by addition of a single amino acid.

Community Reintegration Problems Among Veterans and Active Duty Service Members With Traumatic Brain Injury.

OBJECTIVES: To examine community reintegration problems among Veterans and military service members with mild or moderate/severe traumatic brain injury (TBI) at 1 year postinjury and to identify unique predictors that may contribute to these difficulties. SETTING: VA Polytrauma Rehabilitation Centers. PARTICIPANTS: Participants were 154 inpatients enrolled in the VA TBI Model Systems Program with available injury severity data (mild = 28.6%; moderate/severe = 71.4%) and 1-year postinjury outcome data. DESIGN: Prospective, longitudinal cohort. MAIN MEASURES: Community reintegration outcomes included independent driving, employability, and general community participation. Additional measures assessed depression, posttraumatic stress, and cognitive and motor functioning. RESULTS: In the mild TBI (mTBI) group, posttraumatic stress disorder and depressive symptoms were associated with lower levels of various community reintegration outcomes. In the moderate/severe TBI group, cognition and motor skills were significantly associated with lower levels of community participation, independent driving, and employability. CONCLUSION: Community reintegration is problematic for Veterans and active duty service members with a history of TBI. Unique comorbidities across injury severity groups inhibit full reintegration into the community. These findings highlight the ongoing rehabilitation needs of persons with TBI, specifically evidence-based mental healthcare, in comprehensive rehabilitation programs consistent with a chronic disease management model.

Supervision Needs Following Veteran and Service Member Moderate to Severe Traumatic Brain Injury: A VA TBI Model Systems Study.

OBJECTIVE: To characterize supervision levels across residential settings at 1 year post-TBI and explore predictors of supervision in a Veteran and Service-member population. SETTING: Five VA Polytrauma Rehabilitation Centers. PARTICIPANTS: A total of 302 individuals enrolled in the VA TBI Model Systems (TBIMS) research program. DESIGN: Prospective, longitudinal, multisite. MAIN MEASURES: Primary residence and supervision levels measured via scores on the Supervision Rating Scale. For predictive modeling, scores were dichotomized into 2 groups: those that were fully independent/living alone or required only some supervision during the day (independent group, n = 195) and those that required overnight supervision, full-time indirect supervision, and full-time direct supervision (dependent group, n = 107). RESULTS: Thirty-five percent were receiving supervision at 1 year post-TBI across residential settings and 28% were living in alternative settings. Multivariate modeling indicated that older age and longer posttraumatic amnesia (PTA) were predictive of having a need for supervision at 1 year postinjury. CONCLUSIONS: Supervision needs are long-term features of moderate and severe TBI. Results of this study lend support to the shift toward conceptualizing TBI as a chronic disease.

A cell-based screening assay to identify pharmaceutical compounds that enhance the regenerative quality of corneal repair.

The goal of this study was to develop and validate a simple but quantitative cell-based assay to identify compounds that might be used pharmaceutically to give tissue repair a more regenerative character. The cornea was used as the model, and some specific aspects of repair in this organ were incorporated into assay design. A quantitative cell-based assay was developed based on transcriptional promoter activity of fibrotic marker genes ACT2A and TGFB2. Immortalized corneal stromal cells (HTK) or corneal epithelial cells (HCLE) were tested and compared to primary corneal stromal cells. Cells were transiently transfected with constructs containing the firefly luciferase reporter gene driven by transcriptional promoters for the selected fibrotic marker genes. A selected panel of seven chemical test compounds was used, containing three known fibrosis inhibitors: lovastatin (LOV), tyrphostin AG 1296 (6,7-dimethoxy-3-phenylquinoxaline) and SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), and four potential fibrosis inhibitors: 5-iodotubercidin (4-amino-5-iodo-7-(ß-D-ribofuranosyl)-pyrrolo(2,3-d)pyrimidine), anisomycin, DRB (5,6-dichloro-1-ß-D-ribofuranosyl-benzimidazole) and latrunculin B. Transfected cells were treated with TGFB2 in the presence or absence of one of the test compounds. To validate the assay, compounds were tested for their direct effects on gene expression in the immortalized cell lines and primary human corneal keratocytes using RT-PCR and immunohistochemistry. Three "hits" were validated LOV, SB203580 and anisomycin. This assay, which can be applied in a high throughput format to screen large libraries of uncharacterized compounds, or known compounds that might be repurposed, offers a valuable tool for identifying new treatments to address a major unmet medical need. Anisomycin has not previously been characterized as antifibrotic, thus, this is a novel finding of the study.

Chondrogenesis in scleral stem/progenitor cells and its association with form-deprived myopia in mice.

PURPOSE: Previously, we demonstrated that scleral stem/progenitor cells (SSPCs) from mice have a chondrogenic differentiation potential, which is stimulated by transforming growth factor-ß (TGF-ß). In the present study, we hypothesized that chondrogenesis in the sclera could be a possible mechanism in myopia development. Therefore, we investigated the association of form-deprivation myopia (FDM) with expressions in mice sclera representing the chondrogenic phenotype: collagen type II (Col2) and α-smooth muscle actin (α-SMA). METHODS: The mRNA levels of α-SMA and Col2 in cultured murine SSPCs during chondrogenesis stimulated by TGF-ß2 were determined by real-time quantitative RT-PCR (qRT-PCR). The expression patterns of α-SMA and Col2 were assessed by immunohistochemistry in a three dimensional pellet culture. In an FDM mouse model, a western blot analysis and immunofluorescence study were used to detect the changes in the α-SMA and Col2 protein expressions in the sclera. In the RPE-choroid complex, qRT-PCR was used to detect any changes in the TGF-ß mRNA expression. RESULTS: The treatment of SSPCs in vitro with TGF-ß2 for 24 h at 1 or 10 ng/ml led to increased levels of both the α-SMA and Col2 expressions. In addition, we observed the formation of cartilage-like pellets from TGF-ß2-treated SSPCs. Both α-SMA and Col2 were expressed in the pellet. In an in-vivo study, the α-SMA and Col2 protein expressions were significantly increased in the sclera of FDM eyes in comparison to contralateral control eyes. Similarly, the levels of TGF-ß in the RPE-choroid complex of an FDM eye were also significantly elevated. CONCLUSION: Based on the concept of stem cells possessing multipotent differentiation potentials, scleral chondrogenesis induced by SSPCs may play a role in myopia development. The increased expressions of the cartilage-associated proteins Col2 and α-SMA during scleral chondrogenesis may be potential markers for myopia development. In addition, the increased levels of TGF-ß mRNA in the RPE-choroid complex might induce the chondrogenic change in the sclera during myopia development.

Association between health literacy and medical care costs in an integrated healthcare system: a regional population based study.

BACKGROUND: Low health literacy is associated with higher health care utilization and costs; however, no large-scale studies have demonstrated this in the Veterans Health Administration (VHA). This research evaluated the association between veterans' health literacy and their subsequent VHA health care costs across a three-year period. METHODS: This retrospective study used a Generalized Linear Model to estimate the relative association between a patient's health literacy and VHA medical costs, adjusting for covariates. Secondary data sources included electronic health records and administrative data in the VHA (e.g., Medical and DCG SAS Datasets and DSS-National Data Extracts). Health literacy assessments and identifiers were electronically retrieved from the originating health system. Demographic and cost data were retrieved from the VHA centralized databases for the corresponding patients who had VHA use in all three years. RESULTS: In a study of 92,749 veterans with service utilization from 2007-2009, average per patient cost for those with inadequate and marginal health literacy was significantly higher ($31,581 [95 % CI: $30,186 - $32,975]; $23,508 [95 % CI: $22,749 - $24,268]) than adequate health literacy ($17,033 [95 % CI: $16,810 - $17,255]). Estimated three-year cost associated with veterans' with marginal and inadequate health literacy was $143 million dollars more than those with adequate health literacy. CONCLUSIONS: Analyses suggest when controlling for other person-level factors within the VHA integrated healthcare system, lower health literacy is a significant independent factor associated with increased health care utilization and costs. This study confirms the association of lower health literacy with higher medical service utilization and pharmacy costs for veterans enrolled in the VHA. Confirmation of higher costs of care associated with lower health literacy suggests that interventions might be designed to remediate health literacy needs and reduce expenditures. These analyses suggest 17.2 % (inadequate & marginal) of the Veterans in this population account for almost one-quarter (24 %) of VA medical and pharmacy cost for this 3-year period. Meeting the needs of those with marginal and inadequate health literacy could produce potential economic savings of approximately 8 % of total costs for this population.

Large-Scale Survey Findings Inform Patients' Experiences in Using Secure Messaging to Engage in Patient-Provider Communication and Self-Care Management: A Quantitative Assessment.

BACKGROUND: Secure email messaging is part of a national transformation initiative in the United States to promote new models of care that support enhanced patient-provider communication. To date, only a limited number of large-scale studies have evaluated users' experiences in using secure email messaging. OBJECTIVE: To quantitatively assess veteran patients' experiences in using secure email messaging in a large patient sample. METHODS: A cross-sectional mail-delivered paper-and-pencil survey study was conducted with a sample of respondents identified as registered for the Veteran Health Administrations' Web-based patient portal (My HealtheVet) and opted to use secure messaging. The survey collected demographic data, assessed computer and health literacy, and secure messaging use. Analyses conducted on survey data include frequencies and proportions, chi-square tests, and one-way analysis of variance. RESULTS: The majority of respondents (N=819) reported using secure messaging 6 months or longer (n=499, 60.9%). They reported secure messaging to be helpful for completing medication refills (n=546, 66.7%), managing appointments (n=343, 41.9%), looking up test results (n=350, 42.7%), and asking health-related questions (n=340, 41.5%). Notably, some respondents reported using secure messaging to address sensitive health topics (n=67, 8.2%). Survey responses indicated that younger age (P=.039) and higher levels of education (P=.025) and income (P=.003) were associated with more frequent use of secure messaging. Females were more likely to report using secure messaging more often, compared with their male counterparts (P=.098). Minorities were more likely to report using secure messaging more often, at least once a month, compared with nonminorities (P=.086). Individuals with higher levels of health literacy reported more frequent use of secure messaging (P=.007), greater satisfaction (P=.002), and indicated that secure messaging is a useful (P=.002) and easy-to-use (P≤.001) communication tool, compared with individuals with lower reported health literacy. Many respondents (n=328, 40.0%) reported that they would like to receive education and/or felt other veterans would benefit from education on how to access and use the electronic patient portal and secure messaging (n=652, 79.6%). CONCLUSIONS: Survey findings validated qualitative findings found in previous research, such that veterans perceive secure email messaging as a useful tool for communicating with health care teams. To maximize sustained utilization of secure email messaging, marketing, education, skill building, and system modifications are needed. These findings can inform ongoing efforts to promote the sustained use of this electronic tool to support for patient-provider communication.

Clathrin-mediated hemoglobin endocytosis is essential for survival of Leishmania.

Leishmania is auxotroph for heme. Previously, we have shown that Leishmania acquire heme from the degradation of endocytosed hemoglobin via a specific receptor located in the flagellar pocket. Here, we report the cloning and expression of clathrin heavy chain from Leishmania (Ld-CHC) and provide evidences that Ld-CHC is localized in flagellar pocket and regulates Hb-endocytosis in Leishmania. Kinetic analysis of Hb trafficking in GFP-Ld-CHC overexpressed Leishmania reveals that Hb is internalized through Ld-CHC coated region and remains associated with Ld-CHC containing vesicles at early time points of internalization and subsequently starts dissociating from Hb-containing vesicles at later time points indicating that clathrin-coating and uncoating regulate Hb trafficking in Leishmania. Interestingly, overexpression of dominant negative mutant of clathrin heavy chain of Leishmania (GFP-Ld-CHC-Hub) blocks the Hb internalization and causes severe growth defect in parasite. Moreover, we have shown that chlorpromazine, a pharmacological agent, blocks Hb internalization in Leishmania by depolymerizing Ld-CHC and thereby inhibits the growth of the parasites. Taken together, our results have shown that Hb endocytosis in Leishmania is a clathrin dependent process and is essential for the survival of the parasites.

Dynamics of Cl + propane, butanes revisited: a crossed beam slice imaging study.

We report velocity-flux contour maps for H-D abstraction in selected Cl + alkane reactions measured by means of crossed beam scattering combined with universal DC slice imaging. The studied hydrocarbons are propane and its two selectively deuterated isotopologues, namely 1,1,1,3,3,3-propane-d6 and 2,2-propane-d2, n-butane and isobutane (2-methyl-propane), with detection of the hydrocarbon radical product by 157 nm single photon ionization. Data are obtained at collision energies of 12-13 kcal mol(-1) using a high-density atomic chlorine radical source combining Cl2 photolysis with ablation. All presented scattering distributions involving secondary and tertiary abstractions show distinct differences. Their comparisons allow for revisiting the dynamical picture of these reactions in terms of the nature of the abstraction sites, radical product energy disposal, and H vs. D abstraction. Results are discussed in the light of previous work and ab initio thermochemical calculations, along with proposals to future directions for investigation.

Effects of a national safe patient handling program on nursing injury incidence rates.

OBJECTIVE: The objective of the study was to identify which components of a system-wide safe patient handling (SPH) program reduced musculoskeletal injury (MSI) due to patient handling among nurses. METHODS: The 3-year longitudinal study from 2008 to 2011 used a pretest-posttest design. The study was conducted in the Veterans Health Administration, and all medical centers participated. The outcome was 2011 MSI incidence rates due to patient-related handling for nurses, expressed as injuries per 10 000 full-time employees. RESULTS: Three organizational risk factors, bed days of care, facility complexity level, and baseline MSI incidence rate, were significantly associated with MSI incidence rate and explained 21% of its variation. Five SPH components, including deployment of ceiling lifts and other new technologies, peer leader effectiveness, competency in SPH equipment use, facility coordinator link with safety committee, and peer leader training, uniquely accounted for an additional 23% of the total variation. CONCLUSIONS: Findings provide evidence to support the effectiveness of a multicomponent approach to SPH programs given contextual considerations.

Development and experimental validation of 3D QSAR models for the screening of thyroid peroxidase inhibitors using integrated methods of computational chemistry.

The intricate network of glands and organs that makes up the endocrine system. Hormones are used to regulate and synchronize the nervous and physiological systems. The agents which perturbate an endocrine system are called endocrine disruptors and they can eventually affect cellular proliferation and differentiation in target tissues. A subclass of endocrine disruptors known as thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs) influence the hypothalamo-pituitary-thyroid axis or directly interfere with thyroid function by binding to thyroid hormone receptors. Thyroid hormone levels in circulation are now included in more test guidelines (OECD TG 441, 407, 408, 414, 421/422, 443/416). Although these might be adequate to recognize thyroid adversity, they are unable to explain the underlying mechanism of action. Thyroid peroxidase (TPO) and sodium iodide symporter (NIS), two proteins essential in the biosynthesis of thyroid hormones, are well-accepted molecular targets for inhibition. The screening of a large number of molecules using high throughput screening (HTS) requires a minimum quantity of sample, cost, and time consuming. Whereas 3-dimensional quantitative structure-activity relationship (3D-QSAR) analysis can screen the TDCs before synthesizing a compound. In the present study, the human TPO (hTPO) and NIS (hNIS) structures were modelled using homology modeling and the quality of the structures was validated satisfactorily using MD simulation for 100ns. Further, 190 human TPO inhibitors with IC50 were curated from Comptox and docked with the modelled structure of TPO using D238, H239 and D240 centric grid. The binding conformation of a molecule with low binding energy was used as a reference and the rest other molecules were aligned after generating the possible conformers. The activity-stratified partition was performed for aligned molecules and training set (139), test set (51) were defined. The machine learning models such as k Nearest Neighbor (kNN) and Random Forest (RF) models were built and validated using external experimental dataset containing 10 molecules. Among the 10 molecules, all 10 molecules were identified as TPO inhibitors and demonstrated 100 % accuracy qualitatively. To confirm the selective TPO inhibition all 10 molecules were docked with the modelled structure of hNIS and the results have demonstrated the selective TPO inhibition.

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Interaction of clusterin and matrix metalloproteinase-9 and its implication for epithelial homeostasis and inflammation.

Uncontrolled increases of matrix metalloproteinase-9 (MMP-9) activity have been causally linked to epithelial barrier disruption and severe symptoms of inflammatory diseases such as dry eye (DE). The data presented here show that the anti-inflammatory, cytoprotective intracellular and extracellular chaperone protein clusterin (CLU) interacts with MMP-9 both inside and outside epithelial cells. CLU bound very strongly to active MMP-9, with an affinity constant K(D) of 2.63 nmol/L. Unexpectedly, CLU had a much higher affinity for pro-MMP-9 than for active MMP-9 or pro-MMP-2, requiring the N-terminal propeptide domain of pro-MMP-9. The significance of the interaction between CLU and MMP-9 was demonstrated by the observation that CLU prevents stress-induced MMP-9 aggregation and inhibits MMP-9 enzymatic activity. Furthermore, CLU inhibited MMP-9-mediated disintegration of the tight junction structure formed between human epithelial cells. Additionally, CLU inhibited enzymatic activities of MMP-2, MMP-3, and MMP-7. Treatment with proinflammatory cytokines, which are known to increase MMP-9 transcription under inflammatory conditions, reduced the expression of CLU in human epithelial cells. Similarly, in a mouse model of human DE, inflammatory stress depleted CLU in the ocular surface epithelium but allowed MMP-9 to prevail therein. The present results thus provide novel insights into previously unrecognized mechanisms by which CLU maintains fluid-epithelial interface homeostasis, thereby preventing the onset of inflammatory conditions, especially where MMP-9 is actively involved.

A mathematical model for maximizing the value of phase 3 drug development portfolios incorporating budget constraints and risk.

We describe a value-driven approach to optimizing pharmaceutical portfolios. Our approach incorporates inputs from research and development and commercial functions by simultaneously addressing internal and external factors. This approach differentiates itself from current practices in that it recognizes the impact of study design parameters, sample size in particular, on the portfolio value. We develop an integer programming (IP) model as the basis for Bayesian decision analysis to optimize phase 3 development portfolios using expected net present value as the criterion. We show how this framework can be used to determine optimal sample sizes and trial schedules to maximize the value of a portfolio under budget constraints. We then illustrate the remarkable flexibility of the IP model to answer a variety of 'what-if' questions that reflect situations that arise in practice. We extend the IP model to a stochastic IP model to incorporate uncertainty in the availability of drugs from earlier development phases for phase 3 development in the future. We show how to use stochastic IP to re-optimize the portfolio development strategy over time as new information accumulates and budget changes occur.

Crossed-beam slice imaging of Cl reaction dynamics with butene isomers.

We present a crossed-beam imaging study of the reaction of chlorine atoms with several butene isomers. A high-intensity pulsed ablation Cl source is used with DC slice imaging and single-photon ionization detection at 157 nm to record the velocity-flux contour maps for these reactions. The target unsaturated hydrocarbons are 1-butene, trans-2-butene, cis-2-butene, and isobutene (2-methylpropene). Data are obtained at collision energies of ~13.0 kcal·mol(-1). Distinct differences in the scattering distributions and in particular the coupling of angular and translational energy release provide insight into the dynamics of this little-studied class of reactions. We find that these distributions reflect the energetics for competition between addition/elimination and direct abstraction in line with ab initio thermochemical data. A possible role for Cl atom roaming mediating the addition/elimination pathway is suggested.