Lack Of Response Research Articles

Molecular basis for the disease-modifying effects of belimumab in systemic lupus erythematosus and molecular predictors of early response: blood transcriptome analysis implicates the innate immunity and DNA damage response pathways

ObjectivesBelimumab is a putative disease-modifying agent in systemic lupus erythematosus (SLE), yet the molecular underpinnings of its effects and the ability to predict early clinical response remain unexplored. To address...

Deciphering the landscape of triple negative breast cancer from microenvironment dynamics and molecular insights to biomarker analysis and therapeutic modalities.

Triple negative breast cancer (TNBC) displays a notable challenge in clinical oncology due to its invasive nature which is attributed to the absence of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor (HER-2). The heterogenous tumor microenvironment (TME) of TNBC is composed of diverse constituents that intricately interact to evade immune response and facilitate cancer progression and metastasis. Based on molecular gene expression, TNBC is classified into four molecular subtypes: basal-like (BL1 and BL2), luminal androgen receptor (LAR), immunomodulatory (IM), and mesenchymal. TNBC is an aggressive histological variant with adverse prognosis and poor therapeutic response. The lack of response in most of the TNBC patients could be attributed to the heterogeneity of the disease, highlighting the need for more effective treatments and reliable prognostic biomarkers. Targeting certain signaling pathways and their components has emerged as a promising therapeutic strategy for improving patient outcomes. In this review, we have summarized the interactions among various components of the dynamic TME in TNBC and discussed the classification of its molecular subtypes. Moreover, the purpose of this review is to compile and provide an overview of the most recent data about recently discovered novel TNBC biomarkers and targeted therapeutics that have proven successful in treating metastatic TNBC. The emergence of novel therapeutic strategies such as chemoimmunotherapy, chimeric antigen receptor (CAR)-T cells-based immunotherapy, phytometabolites-mediated natural therapy, photodynamic and photothermal approaches have made a significant positive impact and have paved the way for more effective interventions.

What Has the Sudden Unexpected Infant Death and Sudden Death in the Young Case Registry Learned About Consenting Families for DNA Banking and/or Genomic Research?

Since 2015, the Sudden Unexpected Infant Death (SUID) and Sudden Death in the Young (SDY) Case Registry has characterized sudden and unexpected deaths among young people (0-20 years). Families may provide informed consent to save biospecimens for banking and/or genomic research. We reviewed all consent-eligible cases to describe the frequency, time from death to consent, type (paper, phone, or electronic), and staffing method (Medical Examiner Office-based bereavement counselor vs outsourced genetic counselor). Of 5438 cases from January 2015 to January 2022, 3498 (64%) were eligible for consent and 391 (11%) were successfully consented. Half (54%) were obtained within 60 days of the death, 39% within 48 hours. Most were paper based (73%); 23% were obtained by phone, and 4% electronically. Consent rates varied by site from 3% to 66%. Higher consent rates were achieved within a Medical Examiner Office by a social worker or death investigator. Only 3% of consents attempted by a contracted genetic counselor were successful. Identified barriers include lack of available contact information, inability to reach family using the collected information, and lack of response when contacted. Consent rates were highest shortly after death when families were contacted by the Medical Examiner Office as part of bereavement outreach.

Developing an integrated and collaborated evaluation index system for crude oil supply chains: A case study from China

The crude oil supply chain involves production, transportation, refining, marketing, storage and trade with numerous interconnected links and complex interrelationships. Enhancing the overall value of crude oil supply chains depends on the coordinated development of their upper, middle and lower reaches. However, the absence of a scientific and objective evaluation index system for collaborative development within the crude oil industry precludes identification of weak links that require improvement, thereby impeding supply chain development decision-making. This study aims to construct an integrated and coordinated development evaluation index system for crude oil supply chains, providing a crucial reference framework for scientific evaluation, guidance, and assessment of crude oil supply chains. Taking China's crude oil supply chain as a case study, this research analyzes the current state of crude oil supply chain research and employs the 5 dimensions of SCOR as the primary evaluation index to examine production, transportation, refining, marketing, storage, and trading. An evaluation index system for integrated and coordinated development of the crude oil supply chain is presented, followed by the development of an evaluation model combining the combination weighting method with the TOPSIS approach. The index system and model established in this study are applied to PetroChina. The findings indicate that PetroChina achieved the highest integration and coordination level in 2021, with a score of 0.578, attributed to optimal supply chain efficiency; conversely, the integration coordination degree in 2017 was subpar, with a score of only 0.468, primarily due to the supply chain's lack of responsiveness. This evaluation index system and model offer a comprehensive assessment of the development in each link and aspect within the supply chain, which can intuitively reflect the weak points of the supply chain and provide essential theoretical support for integrated and coordinated development of PetroChina.

Differential impact of optogenetic stimulation of direct and indirect pathways from dorsolateral and dorsomedial striatum on motor symptoms in Huntington's disease mice

The alterations in the basal ganglia circuitry are core pathological hallmark in Huntington's Disease (HD) and traditionally linked to its sever motor symptoms. Recently it was shown that optogenetic stimulation of cortical afferences to the striatum is able to reverse motor symptoms in HD mice. However, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor phenotype is still not clear. Here, we aim to uncover the contributions of these striatal subcircuits to motor control in wild type (WT) and HD mice by using the symptomatic R6/1 mice. We systematically evaluated locomotion, exploratory behavior, and motor learning effects of the selective optogenetic stimulation of D1 or A2A expressing neurons (direct and indirect pathway, respectively), in DLS or DMS. Bilateral optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS resulted in subtle locomotor enhancements, while unaltering exploratory behavior. Additionally, bilateral stimulation of the indirect pathway from the DLS improved performance in the accelerated rotarod task, suggesting a role in motor learning. In contrast, in HD mice, stimulation of these pathways did not modulate any of these behaviors. Overall, this study highlights that selective stimulation of direct and indirect pathways from DLS and DMS have subtle impact in locomotion, exploratory activity nor motor learning. The lack of responses in HD mice also suggests that strategies involving cortico-striatal circuits rather than striatal output circuits might be a better strategy for managing motor symptoms in movement disorders.

Notalgia Paresthetica Dermatologist Report of Symptom Burden and Treatment: Results from a Physician Survey.

Notalgia paresthetica (NP) is a sensory neuropathy characterized by chronic pruritus, skin pain, and other pathologic sensations affecting the mid-to-upper back. NP may be under-recognized and under-diagnosed, with limited data available on its symptom presentation and treatment patterns. NP-DERM was an internet-based survey of dermatologists (n = 650) from 8 different countries on their perspectives on NP symptoms and current treatment practices. Dermatologists typically treated a median of 12 patients with NP per month. Dermatologists reported that itch (pruritus) was the most common symptom for their patients with NP, followed by hyperpigmentation and sensitive skin. The most burdensome NP symptom was pruritus, followed by burning or hot sensation, and painful or raw skin. The most prescribed treatments included non-medicated skin care, topical corticosteroids, oral antihistamines, medicated topicals, and gabapentin or pregabalin. Physicians reported low satisfaction with available treatments. The most common reason for physicians to discontinue patients' therapy was lack of response.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Implementasi P5 PPRA dalam Pengembangan Minat dan Bakat Siswa MI YMI Wonopringgo 03 Kabupaten Pekalongan

This study explores the implementation of the Pancasila Student Profile Strengthening Project (P5) and Rahmatan lil 'Alamin Student Profile (PPRA) within the Merdeka curriculum at MI YMI Wonopringgo 03, Pekalongan Regency. The research aims to address the challenges in nurturing and developing students' interests and talents at Madrasah Ibtidaiyah (MI). Initial observations identified several issues affecting student engagement, including laziness, lack of responsiveness, and a tendency to give up easily. These behaviors hinder the optimal development of students' potential. Through a comprehensive analysis, the study examines how innovative teaching approaches and collaborative planning can enhance student engagement and achievement. The findings highlight the significance of integrating religious practices with modern educational strategies to foster a holistic learning environment. The Merdeka curriculum's emphasis on religious habituation is found to be instrumental in motivating students and uncovering their latent talents. MI YMI Wonopringgo 03, known for its consistent student achievements at various levels, serves as a model for effective implementation of the curriculum. The study concludes that tailored educational models and methods significantly contribute to the development of students' interests and talents, leading to improved educational outcomes and the overall quality of the institution. This research underscores the importance of continuous innovation and personalized learning approaches in education, particularly within religious institutions. The successful integration of P5 and PPRA within the Merdeka curriculum at MI YMI Wonopringgo 03 offers valuable insights for educators and policymakers aiming to enhance student potential and academic performance in similar educational settings.

Strategi Guru Taman Pendidikan Al- Qur’an (TPQ) Al-Mujahadah Dalam Mengatasi Kejenuhan Belajar Membaca Alqur’an Pada Anak di Dusun Sepinggan Gelik

This study stems from the strategies used by teachers of the Al-Qur'an Education Park in Overcoming the Boredom of Learning to Read the Qur'an of Children in Sepinggan Gelik Hamlet, Semparuk District in 2023. This study aims, 1) to describe and analyze the implementation of learning at the Al-Mujahadah Al-Qur'an Education Park (TPQ) in overcoming the boredom of learning to read the Qur'an in children in Sepinggan Gelik Hamlet, Semparuk District 2023. 2) to know what are the supporting and inhibiting factors in the implementation of learning Taman Pendidikan Al-Qur'an (TPQ) Al-Mujahadah in overcoming boredom in learning to read the Qur'an in children in Sepinggan Gelik Hamlet, Semparuk Subdistrict. This research uses a qualitative approach. The research subjects were two teachers of the Al-Qur'an education park and 2 students. Data collection techniques in this study are: Observation, Interview, and Documentation. While data analysis techniques used data reduction, data presentation, verification and conclusion drawing. The results of the study are: a) Al-Mujahadah Quranic Education Park is held on Monday, Wednesday, and Thursday at 15.00-16.45. b) congregational asar prayer, prayer and roll call c) children write Al-Qur'an verses and draw. d) rest e) material f) prayer. The supporting factor for the implementation of this learning is the discussion and cooperation between the Al-Qur'an education park teachers and the mosque administrators and the community. Second, the inhibiting factors in the implementation of the Al-Qur'an Education Park are the lack of response from children so that it is rather difficult to apply the strategies to be used, and the large amount of arrears in dues from students, as well as teachers lacking mastery of technology so it is difficult to find references via the internet.

THE ROLE OF ARTIFICIAL INTELLIGENCE IN DIGITAL ENVIRONMENT OF LIBRARIES

AI in academic libraries has been a topic of interest. In recent years. Artificial Intelligence has been making its way into libraries and transforming the way they operate Artificial Intelligence technology is being used to improve the library experience for patterns, enhance library services, and streamline library operations. The study found that some college and research libraries show interest engage with Artificial Intelligence most notably Delhi Centre Libraries. The library collection project collaboration starts with future uses from academic librarians but the study also indicated a lack of response are awareness of the current IA trend.

Long-term follow-up of levonorgestrel intrauterine device for atypical hyperplasia and early endometrial cancer reveals relapse characterized by immune exhaustion.

Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited. Follow-up data from patients in our prospective phase II trial of LIUD for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse. Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at six months, premenopausal status, and Hispanic ethnicity (p<0.05), but only six-month response status remained a significant predictor in a multivariate model (p=0.023). LIUD increased abundance of NK cells (DMCP-counter score=46.13, FDR=0.004) and cytotoxic lymphocytes (DMCP-counter score=277.67, FDR=0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC=1.62, FDR=0.025) and GZMA (log2FC=2.47, FDR=0.008). NK cells were reduced at relapse (DMCP-counter score=-55.96, FDR=0.02). Immune-related pathways (IFNα-response and TGFβ-signaling) were enriched at relapse (FDR<0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR<0.05). Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for non-surgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion.

Single cell characterization of persistent cells upon immunotherapy treatment in colorectal and endometrial tumors: The SERPENTINE trial.

3139 Background: Immune checkpoint inhibitor (ICI) therapy has proved efficacy in MSI colorectal (CRC) and endometrial cancer (EC), but its use in MSS tumors remains a challenge. As the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both pathways may have additive or synergistic activity in comparison with single PD-1/PD-L1 inhibition in MSS and MSI CRC and EC tumors, while single cell characterization of persistent cells upon treatment would enable to describe cell populations and build a detailed single-cell map of the immune, tumor and stromal cell composition. A single dose of tremelimumab (Trem) 300mg, while maintaining a similar overall exposure, has 3- to 4-fold higher Cmax compared to 4 doses of Trem 1 mg/kg, which may have the potential for better anti-tumor activity while potentially avoiding cumulative toxicity. Here we present the results of patients (pts) with refractory ICI-naïve MSS EC and CRC treated with Dur plus Trem and the characterization of immune and persistent cells with longitudinal single-cell analyses. Methods: Pts with advanced MSS/pMMR CRC and EC that have progressed during or after standard therapy with measurable disease per RECIST 1.1, ECOG ≤1, were treated with Dur 1500mg plus Trem 300mg at Week 0, followed by Dur 1500 mg Q4W. Response rate was correlated with transcriptome and T cell repertoire dynamics measured at single-cell level from freshly processed biopsies at three different timepoints: baseline, upon treatment and at progression. Results: 24 samples for single-cell analysis were obtained (4 MSS CRC and 4 MSS EC). The response rate (RR) was 0%, while disease control rate was 12.5%. Despite the lack of response, we found a massive shift in the immune tumor microenvironments of all patients. Following treatment, immune cell composition shifted to increased frequency of effector-memory, proliferating CD8+ cells and CD4+ cells, surprisingly, with enriched T helper phenotypes. Both lineages showed strong signals of exhaustion. The integration of matched T cell receptor (TCR) data pointed to an infiltration of new clonotypes, rather than the expansion of pre-existing tumor-resident T cells, with distinct degrees of dysfunctional phenotypes between the clones. Intriguingly, expanded clonotypes could be detected and monitored in peripheral blood cells using ultra-deep TCR sequencing. Conclusions: Dual treatment with Dur and Trem does not result in an improved RR in patients with refractory MSS/pMMR CRC and EC, despite profound dynamics in the tumor infiltrating immune cells landscape. The infiltration of CD4+ T helper cells provides mechanistic insights of immune evasion, a potential avenue to treat MSS/pMMR tumors. Clinical trial information: 2021-004061-13 .

RNA-Seq based gene expression profiling of baseline and on-treatment breast tumors to predict response to HER2-directed therapy, without chemotherapy (TBCRC026).

530 Background: Robust biomarkers are needed to personalize treatment in early stage HER2-positive breast cancer. The TBCRC026 trial (n=83) demonstrated that early metabolic changes on FDG-PET/CT [&gt;40% decline in SULmax at day 15 post treatment initiation (C1D15); C1D15 SULmax] were associated with response to neoadjuvant trastuzumab/pertuzumab (HP), without chemotherapy, in an ER-negative, HER2-positive cohort (NCT01937117). We investigated the association of RNA sequencing (RNAseq)-based gene expression signatures (GES) at baseline and on-treatment (C1D15), with early metabolic change on PET/CT and clinical outcomes. Methods: RNAseq (664 GES) was performed on baseline (n=56) and C1D15 (n=31) tumor biopsies (25 paired samples available). Association with pCR following HP (secondary), PET/CT parameters and survival (exploratory) was studied. Gene expression changes between baseline and C1D15 samples were tested by Wilcoxon signed-rank test. Association between GES and PET/CT parameters and GES with pCR were evaluated using logistic regression models. Cox regressions were performed to study the association between PET/CT SULmax at C1D15 and a B cell signature and relapse-free survival (RFS). The likelihood ratio test was used to compare the prognostic ability of two nested Cox models. Results: Both RNAseq and clinical outcomes were available in 53/83 patients. HER2-enriched (HER2-E) intrinsic subtype comprised 71% (40/56) of cases at baseline and 61% (19/31) at D15; basal subtype for 27% (15/56) and 39% (12/31), respectively. pCR rate was 19% (10/53) with all but one exhibiting HER2-E subtype. One basal-like sample underwent pCR, with downregulation of HER2 amplicon and IgG signatures slightly more prominent. Gene expression changes from baseline to C1D15 were analyzed; ERBB2was downregulated after HP (p = 0.007), B cell signatures, CD4, CD8, natural killer cells and Treg cells were significantly upregulated at C1D15. GES associated with 40% decline in SULmax at C1D15 included ERBB2 amplicon genes ( ERBB2, GRB7) and correlation to the HER2-E subtype, whereas basal-like signatures were significantly associated with lack of response on PET at C1D15. Univariate logistic regression analysis suggested that FOS-JUN, fibroblast and B cell GES at baseline were significantly associated with pCR (p=&lt;0.05). Finally, the addition of a B cell signature improved the prognostic value of C1D15 SULmax on PET/CT for RFS (p &lt; 0.05). Conclusions: In this unique cohort with ER-negative, HER2-positive breast cancer treated with neoadjuvant HP without chemotherapy, HER2-E tumors and those with increased immune signaling were more likely to respond to HER2-directed therapy. Combining C1D15 SULmax on PET/CT and a B cell signature provided improved prognostic information and should be further explored as candidate biomarkers in this setting. Clinical trial information: NCT01937117 .

Long-term efficacy of high-dose imatinib in Hispanic patients without access to second-generation tyrosine kinase inhibitors treated in LATAM centers.

6512 Background: Treatment for patients with chronic myeloid leukemia (CML) had a benchmark with the introduction of imatinib, a tyrosine kinase inhibitor (TKI). Nevertheless, resistance due to genetic mutations in the BCR::ABL1 kinase receptor remains relatively common for many patients, leading to failure, lack of response, or suboptimal response. Ideally, to bypass genetic resistance, guidelines recommend switching to a second-generation TKI, but for many developing countries, socioeconomic barriers hinder the possibility of switching medication. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. Methods: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to standard-dose imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights and depicted the survival curves and median using the Kaplan-Meier estimator. Our primary outcome was overall survival (OS) at 150 months, defined as the number of deaths once patients had reached treatment response based on parameters of the European Leukemia Net Guidelines for CML. Our secondary outcomes were disease-free survival (DFS) at 150 months, defined as the number of months after patients achieved either major molecular response or deep molecular response, and adverse events that included gastrointestinal, dermatologic, hematologic, and others. Results: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. While we found no difference in the 150-month risk in both OS and DFS (Table), patients receiving second-generation TKI had an increase in median survival of OS ( p-value = 0.009). No difference was found in the median survival of DFS ( p-value = 0.55). No difference was found in either hematologic, gastrointestinal, dermatologic, or other adverse events (p-values of 0.39, 0.94, 0.24, and 0.33, respectively). Conclusions: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. However, If impossible, our findings suggest that patients treated with high-dose imatinib have a similar OS and DFS prognosis to those receiving a second-generation TKI. [Table: see text]

TRANSFORMASI E-GOVERNMENT DALAM PERSETUJUAN BANGUNAN GEDUNG:

The aim of this research is to determine the application of e-government in building approval services through SIMBG at the Kendari City Investment and One-Stop Integrated Services Service. Researchers used descriptive qualitative research methods. There were 9 informants in this study who were determined using purposive sampling techniques. Data collection techniques through in-depth interviews and documentation studies. Building Approval Services through SIMBG at the Kendari City One-Stop Integrated Services and Investment Service can be seen from: 1) Physical evidence of the availability of good and adequate public service locations. 2) The Reliability Dimension (reliability) of the Kendari City one-stop capital investment and service department is still not in accordance with applicable regulations and SOPs. 3) Responsiveness, which is still not good, can be seen from the lack of response by employees to complaints or complaints from the public in services related to the PBG permit application process through SIMBG. 4) The insurance dimension is good, as seen from the existence of several guarantees, namely data and document security guarantees, PBG document authenticity guarantees and service guarantees. 5) Empathy, this can be seen from the lack of professionalism of employees towards applicants regarding PBG services through SIMBG.

Cancer-related pain experienced in daily life is difficult to communicate and to manage - for patients and for professionals.

The aim of this study was to gain qualitative insight into cancer patients' experiences, explanations, and management strategies regarding their cancer-related pain (CP). Seventeen patients with CP were interviewed using a semi-structured interview approach. Braun and Clarke's thematic analysis method was used to analyze the transcribed interviews. The patients all participated in cancer rehabilitation courses arranged by the research clinic at The Danish Knowledge Centre for Rehabilitation and Palliative Care. Three themes were identified: (1) Explaining CP: Patients found it difficult to explain how they experienced their pain. They lacked words, and they frequently used invasive metaphors such as "Pain feels like a heart attack" (2). Strategies and barriers to the management of CP: Initiatives provided by healthcare professionals (HCPs) were perceived as insufficient, and the patients missed guidance in both pharmacological and non-pharmacological approaches to pain management. Several saw medicine as unnatural for their body, and they focused on side effects and the medicine affecting their quality of life. (3) Responsibility for managing CP: A lack of responsiveness from the HCPs and taking on responsibility for pain management were experienced by several of the patients. The patients expressed uncertainty about whom to contact for help with the management of their CP. The patients' difficulties in explaining, understanding, and communicating their pain and pain management contributed to insufficient pain management. They were also uncertain about who had the responsibility to help them to achieve pain relief. These results share the evidence drawn from studies on patients with chronic non-cancer pain. This qualitative study highlights the need for having more focus on a common language and shared understanding between patients and HCPs. It also underpins the importance of HCPs to assume their responsibility to help patients manage their pain conditions.

Preweaning Purified Fucoidan Drench: Effects on Growth, Immune Response, and Intestinal Morphology in Weaned Piglets

Weaning stress imposes considerable physiological challenges on piglets, often manifesting in intestinal disturbances, such as inflammation and compromised barrier function, ultimately affecting growth and health outcomes. While conventional interventions, including antimicrobials, have effectively mitigated these sequelae, concerns surrounding antimicrobial resistance necessitate the exploration of alternatives. Fucoidan, derived from brown seaweed, offers promise due to its antioxidant and anti-inflammatory effects. Previous research has been limited to the in-feed supplementation of partially purified fucoidan extracted from brown seaweed. The focus of the present study is assessing the effect of a preweaning drench with highly purified (85%) fucoidan on piglet growth, immune response, and intestinal morphology post-weaning. Forty-eight male piglets at 17 ± 3 days of age (5.67 ± 0.16 kg) were assigned to a saline (control), fucoidan, or antimicrobial group, receiving treatment as a single 18 mL oral drench three days before weaning. Monitoring for seven days post-weaning included body weight measurements, blood sample collection for the inflammatory protein assay, and small intestine morphological analysis. The findings revealed that the preweaning fucoidan drench did not elicit adverse effects on piglets. However, neither fucoidan nor antimicrobial drenches significantly enhanced growth parameters, immune markers, or intestinal morphology compared to that of the control-treated piglets (p &gt; 0.05). The lack of response may be attributed to the high health status of the experimental cohort and the limitation of a single dosage. Future research should consider a more challenging production setting to evaluate the viability and optimal application of fucoidan as an antimicrobial alternative in the pig industry.

Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1–FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1–FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117.

Adverse effects of Typbar-typhoid conjugated vaccine in children vaccinated in university of Lahore teaching hospital

Objective: To determine the frequency of adverse effects of Typbar TCV in children vaccinated in Hospital. Study design: Descriptive study Place &amp; duration of study: Department of Pediatrics outpatient clinic, from 1 February to 2021 to 3rd March 2021. Methodology: Children aged 9 months to 15 years of age either gender coming for vaccination from 1st Feb-2021 to 17th Feb-2021 was included in study. Post vaccination Observation for 30 minutes was done for all children in hospital and were followed after 14 days on telephone for any local or systemic adverse effect after vaccination. Complications systemic and local were documented on proforma. All data was analyzed using SPSS 22. P-value calculation for change in percentage of adverse effects in the different age groups and gender Chi-square test was used. Results: In our study, total 835 children were enrolled out of which 666 responded. Contact with 169 children was not possible because their lack of response and unavailability. Mean age was 4.9±4.06 years. Regarding local adverse effects pain at site of injection was present in 30% children. Other local site reaction includes swelling in 17.7%, redness in 3% and limitation of movement in 2.4%. Systemic adverse effects included fever in 20.4%. Headache was present in 0.6% children. GI symptoms present in 0.9%. Conclusion: This study concluded that Typbar-TCV Typhoid Vi conjugate vaccine is safe among children aged 9 months to 15 years.

T-Cell Characteristics Impact Response and Resistance to T-Cell-Redirecting Bispecific Antibodies in Multiple Myeloma.

Bispecific antibodies (BsAb) directed against B-cell maturation antigen (teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated patients with multiple myeloma. However, mechanisms underlying primary and acquired resistance remain poorly understood. The anti-multiple myeloma activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from patients with multiple myeloma. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from patients with multiple myeloma who were treated with these BsAb. In ex vivo killing assays with 41 BM samples from BsAb-naive patients with multiple myeloma, teclistamab- and talquetamab-mediated multiple myeloma lysis was strongly correlated (r = 0.73, P < 0.0001). Both BsAb exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/multiple myeloma cell ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab revealed that high frequencies of PD-1+ CD4+ T cells, CTLA4+ CD4+ T cells, and CD38+ CD4+ T cells were associated with primary resistance. Although this lack of response was linked to a modest increase in the expression of inhibitory receptors, increasing T-cell/multiple myeloma cell ratios by adding extra T cells enhanced sensitivity to BsAb. Further, treatment with BsAb resulted in an increased proportion of T cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired antitumor efficacy in ex vivo experiments. Primary resistance is characterized by a low T-cell/multiple myeloma cell ratio and Treg-driven immunosuppression, whereas reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to the development of acquired resistance.