bluuebunny/crossref_metadata_2025 huggingface dataset:
Linker Histone Regulates the Myeloid Versus Lymphoid Bifurcation of Multipotent Hematopoietic Stem and Progenitors
Authors: Guo Shangqin , Karatepe Kutay , Mafra De Faria Bruna , Zhang Jian , Chen Xinyue , Eastman Anna
Published: December 2024

Multipotent hematopoietic stem and progenitor cells (HSPC) give rise to both myeloid and lymphoid cells. The ratio between myeloid and lymphoid cells is controlled according to homeostatic turnover and adjusted in response to physiological signals. Functionally impaired HSPCs often skew toward the myeloid lineage, underlying disease states such as inflammation and cancer. The molecular mechanisms responsible for the myeloid versus lymphoid decision within the multipotent HSPCs remains poorly understood, and intervention strategies to mitigate this lineage skewing are limited. Here we report that linker histone regulates HSPCs at the lymphoid versus myeloid fate bifurcation. Chromatin DNA is packaged as nucleosomes by core histones (H2A, H2B, H3 and H4) and linker histones (H1), with H1 binding to or around the DNA dyad. H1s are highly conserved and their binding stabilizes nucleosomes, increases chromatin folding/compaction, and is associated with a transcriptionally repressed state. While genetic inactivation of any single linker histone genes yields little phenotype, simultaneous inactivation of three H1 genes (H1c-/-/H1dD/D/H1e-/-, TKO) in the hematopoietic lineages severely compromised the lymphoid lineages, as reported by Willcockson et al 2021. However, whether this apparent myeloid skewing originated from HSPCs remains known. We established a doxycycline inducible H1.0 transgene, tagged with GFP, to facilitate the manipulation and tracking of the H1.0 protein. Using this mouse model, we examined the myeloid versus lymphoid fate choice of HSPCs and found that H1.0 high HSPCs favor the lymphoid fate, in association with strengthened nucleosome organization and repression of key myeloid driver genes. Furthermore, H1.0 is turned over in response to interferon signaling, and protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, we propose a molecular model that connects inflammatory signals to the impaired lineage potential of HSPCs resulting in myeloid skewing. Our work uncovers a point of pharmacologic intervention to mitigate myeloid skewed hematopoiesis.
Effect of Granulocyte Colony Stimulating Factor (GCSF) on Survival in Patients with Acute Myeloid Leukemia (AML)
Authors: Desai Devashish , Sampat Parth , Mammadli Mahinbanu , Ghimire Krishna
Published: December 2024

Background:

GCSF is a hematopoietic growth factor used in patients receiving chemotherapy, which is commonly used to prevent chemotherapy-induced neutropenia and neutropenic fever. There is concern that use of GCSF can enhance proliferation of myeloid blasts. Our goal was to analyze the effect of GCSF on survival with patients with AML.

Methods:

TrinetX, a global federated research network, provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with AML. The population was further divided into two groups, based on the receipt of GCSF (filgrastim, pegfilgrastim, lenograstim, eflapegrastim) within 6 months of diagnosis. Further, propensity score matching (PSM) was carried out to match age, sex, race, and severe sepsis. Descriptive analysis was used for demographic data. Kaplan Meier analysis using log-rank test was used for overall survival (OS), and Cox regression used for hazard ratio (HR).

Results:

99,756 patients were identified with AML, out of whom 21.34% (21,293) received GCSF. It was seen that patients who received GCSF were significantly younger (56.2 ± 16.3 vs. 60.5 ± 18.7, p <0.0001). Males were predominant gender in both groups and were significantly higher in receiving GCSF (54% vs. 52%, p <0.0001). Looking into Race, Caucasians (67% vs. 49%, p <0.0001) were predominant race in both groups. African Americans (8% vs. 7%, p<0.0001) and Asians (5% vs. 3%, p <0.0001) were significantly more in the GCSF group, while Unknown races were more in no GCSF group (16% vs. 37%, p <0.0001). Patients who received GCSF were found to have more severe sepsis with or without shock (11% vs. 2%, p<0.0001). Median follow-up was 549 days and 202 days for patients in the GCSF group and not in the GCSF group, respectively. Relapse of AML was significantly more in the GCSF group (25.41% (4,512) vs. 7.26% (5,107), p <0.0001; OR - 4.35 (4.162,4.547)). 47.14% patients died in GCSF group compared to 32.07% in non-GCSF group (p<0.0001). Kaplan Meier curve showed significant separation of curve with median OS shorter in patients who received GCSF (1,079 vs. 2,339 days, p<0.0001; Hazard Ratio - 1.132 (1.106-1.159)). After PSM, 25.50% patients who received GCSF had relapse (25.50 vs. 9.0%, p<0.0001; OR - 3.461 (3.259,3.675)) and 46.48% died (46.48% vs. 33.38%, p<0.0001; HR - 1.263 (1.224,1.304)).

Conclusion:

Our study shows real world data, where use of GCSF in patients with AML has increased risk for relapse as well as death. Overall survival was also shorter for patients who received GCSF. GCSF should be used very diligently in AML cases.
Selective Reversal of ADAR1 Splicing Prevents Leukemia Stem Cell Maintenance In Vivo
Authors: Ma Wenxue , Jamieson Catriona , Pham Jessica , Klacking Emma E , Katragadda Neha , Ruiz Antonio W , Frias Thomas P , La Clair James J. , Morris Sheldon , Kulidjian Anna , Whisenant Thomas
Published: December 2024

Introduction

Acute myeloid leukemia (AML) is characterized by a clonal proliferation of myeloid progenitors with a reduced capacity to differentiate into more mature cellular elements. Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme that is involved in the editing of messenger RNA (mRNA) transcripts (A-to-I RNA editing), which can alter the function of the resulting protein. ADAR1 drives cancer stem cell (CSC) generation and therapeutic resistance in many types of malignancies. As a potent small molecule splicing modulator, Rebecsinib inhibits splicing of ADAR1 into the ADAR1p150 isoform while Fedratinib inhibits JAK/STAT3 mediated activation of ADAR1p150 transcription1, 2.

Methods

To assess the relative ADAR1 inhibitory capacity of Rebecsinib and Fedratinib, humanized sAML mouse models were established with immunomagnetic bead-selected CD34+ cells from primary AML patient samples. Engrafted mice treated with Rebecsinib survived significantly longer compared to those treated with vehicle (p = 0.0003, log-rank test), Fedratinib (p = 0.016, log-rank test), and the combination of Rebecsinib and Fedratinib (p= 0.0002, log-rank test). In comparison, humanized aged normal bone marrow stem cell mouse models established by intravenous transplantation of CD34+ cells (obtained according to IRB-approved protocols from the bone marrow of patients undergoing hip replacement surgery), into NSG-SGM3 mice demonstrated increased human CD34+ cells engraftment in the bone marrow.

Conclusions

The results suggest that inhibition of ADAR1 splice isoform switching may provide a competitive advantage for normal hematopoietic stem cells compared with leukemia stem cells in the bone marrow niche and lay the foundation for developing clinical ADAR1p150 inhibitory strategies.

References1. Crews L, Balaian L, Delos Santos, NP et al. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML. Cell Stem Cell. 2016; 19: 599-612, PMID: 275700672. Crews L, Ma W, Ladel L, et al. Reversal of Malignant ADAR1 Splice Isoform Switching with Rebecsinib. Cell Stem Cell. 2023.
Influence of Gender on Outcomes and Palliative Care Utilization in Patients with Hodgkin's Lymphoma: A Retrospective Study Using the National Inpatient Sample Database
Authors: Shah Raj , Akkawi Abdul Rahman , Mukhtiar Vaibhavi P , Alqam Anas , Karam Wissam , Zakhour Joud
Published: December 2024

KEYWORDS

Hodgkin's lymphoma, palliative care utilization

OBJECTIVE

To assess outcomes, mortality, and palliative care utilization in hospitalized patients.

DESIGN

Retrospective cross-sectional study

SETTING

National Inpatient Database 2019-2021 using ICD-10 codes

Introduction:

Managing Hodgkin's lymphoma patients in the hospital involves various risk factors along with comorbidities. Its clinical outcomes can vary by gender and other factors. The utilization of palliative care services has encouraged risk stratification of patients, which can be challenging. We aim to explore the actual utilization of palliative care services and outcomes of hospitalized Hodgkin lymphoma patients.

Method:

We analyzed data from the National Inpatient Sample to identify patients who were admitted with a diagnosis of Hodgkin's lymphoma from 2019-2021. Among this population, we looked for trends in the utilization of palliative care services and factors affecting outcomes in hospitalized patients. We investigated the role of gender and overall mortality in this cohort.

Results:

A total of 144,614 patients were admitted over 3 years with a diagnosis of Hodgkin's lymphoma. 53.5% were male and 46.5% were female. The in-hospital mortality was around 3.4%, with more deaths in males than females (4% vs. 3%). Gender did not affect the outcomes for respiratory failure. However, males had a higher incidence of Acute Kidney Injury(AKI) (21% vs. 14%), Gastrointestinal(GI) bleeds (5% vs. 4%), and they required more hemodialysis (1.2% vs. 0.8%). Palliative care utilization was 4.8% and was similar for both genders. The trends for utilizing palliative care services improved overall, with 4.2% in 2019, 4.6% in 2020, and 5.1% in 2021, which was statistically significant with a p-value of 0.02.

Conclusion: Our study's preliminary results indicate a higher incidence of AKI, GI bleeding, and the need for hemodialysis in hospitalized male patients. Considering the higher inpatient mortality in males, studies identifying risk factors might be beneficial. Palliative care services can play a crucial role in the overall management of the patient, and increasing utilization trends are encouraging. Considering the limited availability and higher need for palliative care services, studies on risk stratification will help in navigating care for these patients.
Rethinking Caseloads in Sickle Cell Disease Social Work
Authors: Moorman Spencer , Johnson Shirley , Smith Wally R
Published: December 2024

Background

Sickle cell disease, a lifelong inherited condition affecting mostly African Americans, presents multilayered psychosocial challenges affiliated with systemic health inequities and social determinants of health.1 With the strata of psychological, social, and vocational issues that accompany this pain-filled illness, social workers at the National Alliance of Sickle Cell Centers (NASCC) 2022 meeting voiced their concern about administrative and physician lack of clarity regarding their role, varied licensures, expertise, and capacity to cover caseload expectations.2 To illustrate this misunderstanding in reality, a benchmark survey endorsed by the National Alliance of Sickle Cell Centers was distributed to psychosocial providers and social workers of differing qualifications to gather their reported caseloads per year.

Methodology

A NASCC-endorsed survey was distributed to psychosocial provider contacts in the organization's database. Providers of all sickle cell center sizes, from 100 to 800 + patients, were asked to indicate their role and caseload number. Free text boxes were provided for respondents to expand if necessary. Responses from social work and licensed clinical social work roles were filtered from the data using SPSS t-test statistical analysis.

Results

Of the forty social workers (MSW, CSW, LCSW, etc.) who responded to the survey, thirty-one gave a caseload number and nine either didn't answer or were unsure. The range of caseload numbers provided varied greatly (3 minimum to 600 maximum). The mean for nineteen master level social workers (MSW, MSSW, CSW, ASW, LSW, LBSW, LMSW) was 180 caseloads with a Standard Deviation of +/- 151. For the twelve licensed clinical social workers who responded, the mean was 194 with Standard Deviation of +/- 148.

Conclusion

These results are the first to represent perspectives of the social work workforce in the sickle cell space. No significant differentiation in caseload number exists across scope of practice and credentials. Lack of comprehension of the bandwidth needed across psychosocial roles to address the complex needs of patients with sickle cell disease is evident through the voices of those overworked in this field.
Hemophagocytic Histiocytosis in Acute Myeloid Leukemia: A Prospective Study Integrating Clinico-Laboratory and Flow Cytometry Findings
Authors: Paramasivam Sabitha , Sahoo Ranjit Kumar , Bakhshi Sameer , Mendiratta Mohini
Published: December 2024

Introduction:

Hemophagocytic Histiocytosis (HLH), an acute immune activated state described as cytokine storm, diagnosed by both clinical and laboratory parameters in haematological diseases and as complications in cellular therapies and is uniformly related to inferior outcome in the early- as well as late-period. The incidence of HLH in patients of AML is not explored comprehensively in past. In countries with poor health care facilities, the AML-patients, present late and the overall outcome is poor despite younger age. We hypothesized HLH could be contributing to the inferior outcome. In this study, we prospectively looked for HLH in AML patients both clinically as well as by flow cytometry.

Methods:

We evaluated 34 AML patients prospectively in our institute, with the baseline symptoms (fever) with or without organomegaly, serum ferritin levels and flow cytometry (T-cell profiling) in AML patients (n=34). Clinical HLH in our study was defined as, high-grade unremitting fever with elevated ferritin (> 1000 ng/ml). We performed flow cytometry on peripheral blood for the enumeration of T-lymphocytes and their subtypes and correlated with the clinical HLH.

Results:

Median age 35.5 years (range 15-66) with 70% male population. 58% were newly diagnosed and the rest were relapsed/refractory AML patients. Average baseline blast count of 56%, Hb of 8.9 g/dl, TLC of 18,214 /microlitre and serum ferritin of 1301 ng/ml. More commonly seen with NPM1(23%), RUNX1-RUNX1T1(23%) and IDH2R140Q (20%) mutated were in the group. Out of 34 patients, 27 developed clinical HLH during induction chemotherapy. Induction therapy used were 2+5+Ven (two days of daunorubicin, 5 days of ARA-C and 5 days of venetoclax) under a clinical study. Out of 34 patients, 29 exhibited enhanced expression of CD38 along with HLA-DR (70.22%; range: 33.51%-91.46%) on cytotoxic T-cells. In contrast 5 patients did not show a significant proportion of CD38 with HLA-DR (10.26%; range: 5.43%-14.61%). These findings suggest a potential correlation with HLH, as elevated CD38 expression on cytotoxic T cells has been associated with the hyperactivation and proliferative responses seen in HLH, reflecting a state of heightened immune activation and dysregulation. Notably, 1 patient displayed a dim expression of CD38 (98.83%) without HLA-DR. Clinical data with serum ferritin and fever were correlated with the flow cytometric analysis (correlation co-efficient 0.59, p<0.01). In that out of 34 patients, 20 (58%) showed evidence of HLH by flow cytometry as well as clinical HLH.

Conclusion:

Flow cytometry could be useful in identifying HLH at baseline in patients of AML. Further data regarding early mortality, relapse, and survival will be presented in the conference
Bilateral improvement in age-related macular degeneration following unilateral Aflibercept injection
Authors: Karamat Muhammad Irfan , Saleem Hira , Khakwani Minahil , Ahmed Abdullah
Published: December 2024

Background

The "fellow-eye effect" in anti-vascular endothelial growth factor (anti-VEGF) therapy is a rare phenomenon, particularly with aflibercept. This case report documents the first instance of this effect in Pakistan, highlighting its significance in a resource-limited setting where recent regulatory changes have restricted treatment options for age-related macular degeneration (AMD).

Case presentation

A 62-year-old male presented with bilateral central vision loss due to neovascular AMD. Optical Coherence Tomography revealed serous subretinal fluid in both eyes. Due to financial constraints, only the right eye received a single 2 mg intravitreal aflibercept injection. Remarkably, at the four-week follow-up, both eyes showed significant improvement. Visual acuity improved from 6/12 to 6/9 in the treated right eye and from 6/15 to 6/12 in the untreated left eye. OCT scans demonstrated bilateral resorption of subretinal fluid. At three months, complete fluid resorption was observed in both eyes, with visual acuity improving to 6/6 bilaterally.

Conclusions

This case underscores the potential of the "fellow-eye effect" in anti-VEGF therapy, particularly with aflibercept, in treating bilateral AMD. It highlights a possible strategy for optimizing treatment regimens and reducing costs in resource-limited settings. However, it also raises concerns about systemic absorption and potential risks. The findings emphasize the need for further research on the pharmacokinetics of anti-VEGF agents, personalized treatment plans, and alternative therapies. This case is particularly significant in the context of Pakistan's recent ban on bevacizumab, underscoring the urgent need for accessible and affordable AMD treatments in developing countries.
Changes in psychiatric disorder incidence patterns during the COVID-19 pandemic in Korea: a study using the nationwide universal health insurance data
Authors: Han Changwoo , Choi Juho , Jang Hoyeon , Lee Hwa-Young , Benmarhnia Tarik , Oh Juhwan
Published: December 2024

Background

Few studies have evaluated the incidence of various psychiatric disorders during the coronavirus disease (COVID-19) pandemic using hospital visit data for the entire population of a nation. We used Korea’s universal compulsory health insurance data to conduct a descriptive analysis to evaluate changes in psychiatric disorder incidence during the COVID-19 pandemic.

Methods

Hospital visit data related to psychiatric disorders were retrieved from the National Health Insurance Database. First-ever diagnosis for specific psychiatric disorders for each Korean was identified (from January 2015 to February 2023) and monthly age-standardized incidence rates were calculated. An interrupted time-series analysis was used to estimate counterfactual disease incidence rates and observed and counterfactual rates were compared using difference-in-difference framework.

Results

Compared to pre-pandemic period, there was a decrease in the incidence [percentage changes in monthly rate (95% confidence intervals)] of organic mental disorders [-14.6% (-18.4, -10.9)] and psychoactive substance related disorders [-12.9% (-17.5, -8.3)] during the pandemic. However, anxiety disorders [8.8% (3.1, 14.6)], behavioral syndromes associated with physiological disturbances [8.1% (4.2, 11.9)], mental retardation [8.6% (3.0, 14.2)], psychological developmental disorders [19.6% (11.5, 27.7)], childhood- and adolescent-onset behavioral and emotional disorders [45.1% (28.4, 61.8)], and unspecified mental diseases [51.8% (39.8, 63.8)] increased.

Conclusions

Psychological disease incidence patterns changed substantially during the pandemic in South Korea. Various pandemic-related stressors, such as disrupted lifestyles and hospital accessibility, may have influenced these changes. The causes and public health consequences of these changes require further evaluation.
Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma
Authors: Duraj Tomás , Kalamian Miriam , Zuccoli Giulio , Maroon Joseph C. , D’Agostino Dominic P. , Scheck Adrienne C. , Poff Angela , Winter Sebastian F. , Hu Jethro , Klement Rainer J. , Hickson Alicia , Lee Derek C. , Cooper Isabella , Kofler Barbara , Schwartz Kenneth A. , Phillips Matthew C. L. , Champ Colin E. , Zupec-Kania Beth , Tan-Shalaby Jocelyn , Serfaty Fabiano M. , Omene Egiroh , Arismendi-Morillo Gabriel , Kiebish Michael , Cheng Richard , El-Sakka Ahmed M. , Pflueger Axel , Mathews Edward H. , Worden Donese , Shi Hanping , Cincione Raffaele Ivan , Spinosa Jean Pierre , Slocum Abdul Kadir , Iyikesici Mehmet Salih , Yanagisawa Atsuo , Pilkington Geoffrey J. , Chaffee Anthony , Abdel-Hadi Wafaa , Elsamman Amr K. , Klein Pavel , Hagihara Keisuke , Clemens Zsófia , Yu George W. , Evangeliou Athanasios E. , Nathan Janak K. , Smith Kris , Fortin David , Dietrich Jorg , Mukherjee Purna , Seyfried Thomas N.
Published: December 2024

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.
Dry needling as an adjunct treatment to multimodal rehabilitation protocol following rotator cuff repair surgery: a preliminary, randomized sham-controlled trial
Authors: Naseri Faeze , Dadgoo Mehdi , Pourahmadi Mohammadreza , Amroodi Morteza Nakhaei , Azizi Shirin , Shamsi Amirhossein
Published: December 2024

Background

Rotator cuff repair (RCR) is one of the most prevalent procedures to manage rotator cuff tears (RCT). Postoperative shoulder pain is a common complication following RCR and may be aggravated by activation of myofascial trigger points (MTrP) associated with the injury to the soft tissues surrounding the surgical incision. This study aimed to describe a preliminary, randomized, sham-controlled trial to evaluate the effectiveness of implementing 4 sessions of myofascial trigger point dry needling (MTrP-DN) as a muscle treatment approach along with 10 sessions of multimodal rehabilitation protocol (MRh) consisting of therapeutic exercise, manual therapy, and electrotherapy on postoperative shoulder pain, range of motion (ROM), strength, and functional outcome scores for patients following RCR surgery.

Methods

Forty-six patients aged 40–75 following RCR surgery were recruited and randomly allocated into 2 groups: (1) MTrP-DN plus MRh (experimental group), and (2) sham dry needling (S-DN) plus MRh (control group). This trial had a 4-week intervention period. The primary outcome was the Numeric Pain Rating Scale (NPRS) for postoperative shoulder pain. Secondary outcomes were the Shoulder Pain and Disability Index (SPADI), ROM, and strength. The mentioned outcomes were measured at baseline and week 4. In the current study, adverse events were recorded as well.

Results

No statistically significant differences were observed between groups when adding MTrP-DN to MRh for postoperative shoulder pain after 4 weeks of intervention (mean difference 0.32, [95% CI -0.41,1.05], p = 0.37). However, this trial found a small effect size for postoperative shoulder pain. No significant between-group differences were detected in any of the secondary outcomes (p > 0.05) either. We found significant within-group changes in all studied outcome measures. (p < 0.001). This study also reported minor adverse events. following the needling approach.

Conclusion

The lack of statistically significant differences in the outcomes and small clinical significance in shoulder pain highlights the complexity of pain management, suggesting that alternative methodologies may be needed for meaningful clinical benefits. Future studies should consider different control groups, long-term follow ups, larger sample sizes, and more MTrP-DN sessions to better understand their potential impact.

Trial registration

This trial was registered at (https://www.irct.ir), (IRCT20211005052677N1) on 19/02/2022.
Real-World Survival Outcomes in Non–Small Cell Lung Cancer: The Impact of Genomic Testing and Targeted Therapies in a Latin American Middle-Income Country
Authors: Hernandez-Martinez Juan-Manuel , Guijosa Alberto , Flores‐Estrada Diana , Cruz-Rico Graciela , Turcott Jenny , Hernández-Pedro Norma , Caballé‐Perez Enrique , Cardona Andrés F. , Arrieta Oscar
Published: December 2024

PURPOSE

Targeted therapies are indicated for patients with non–small cell lung cancer (NSCLC) and driver tumor mutations. However, real-world studies on the survival benefits of these agents are limited. This study aimed to evaluate the effect of targeted therapies matched to a genomic alteration on the survival of patients with NSCLC.

METHODS

This retrospective study included 446 patients with advanced NSCLC who underwent next-generation sequencing between 2016 and 2023 at the Instituto Nacional de Cancerología in Mexico. The primary outcomes were progression-free survival (PFS) and overall survival (OS).

RESULTS

For the entire cohort, the PFS and OS were 10.71 months (95% CI, 9.35 to 12.06) and 47.77 months (95% CI, 29.67 to 65.86). PFS was significantly longer in patients with actionable mutations treated with targeted therapies (19.41 months [95% CI, 14.27 to 24.55];
P
< .001) than in patients without actionable mutations (6.4 months [95% CI, 4.4 to 8.4]) or not treated with targeted therapies (6.6 months [95% CI, 5.3 to 7.89]). Similarly, OS was significantly longer in patients with actionable mutations treated with targeted therapies (89.69 months [95% CI, 45.54 to 133.84];
P
< .001) than in patients without actionable mutations (17.11 months [95% CI, 8.65 to 25.57]) or not treated with targeted therapies (22.3 months [95% CI, 12.48 to 32.1]). Survival gains were driven by significant improvements in PFS and OS in patients with
EGFR
and
ALK
mutations.

CONCLUSION

This real-world data analysis demonstrated that targeted therapies improve the survival of patients with NSCLC with actionable mutations, which supports a recommendation for widening access to broad-based genomic testing and targeted therapies.
Gemcitabine Cisplatin and Durvalumab Experience in Advanced Biliary Tract Cancers: A Real-World, Multicentric Data From India
Authors: Muddu Vamshi Krishna , Shah Anjali , John Anupa , Raj Abhishek , Bahl Ankur , Rajappa Senthil J. , Raja Thirumalairaj , Ghosh Joydeep , Lavingia Viraj , Vora Amish , Bhargava Prabhat , Ramaswamy Anant , Khan Arif , Sharma Atul , Trikha Mehak , Dhanawat Aditya , Bonda Avinash , Siripurapu Indraja , Mahajan Manoj , Rohatgi Nitesh , Chandrakant Mosale Venkatesha , Gujarathi Himanshu , Vora Manan , Ankathi Sumankumar , Ostwal Vikas S.
Published: December 2024

PURPOSE

Biliary tract cancers (BTCs) are usually diagnosed in advanced stages, where treatment options are either palliative chemotherapy and/or best supportive care. The breakthrough results of the TOPAZ-1 trial demonstrated a 24% decrease in risk of death at 2 years with the addition of durvalumab to chemotherapy.

MATERIALS AND METHODS

This was a multicenter retrospective cohort study conducted across 14 institutions in India. All the patients were diagnosed with advanced BTCs. The primary objective was to assess median overall survival (mOS) with the use of durvalumab in combination with chemotherapy backbone. The patient details, treatment details, laboratory results, and outcome parameters were recorded from the prospectively collected databases.

RESULTS

A total of 148 patients were included with a median age of 57.5 years; 36 (24.3%) patients had borderline Eastern Cooperative Oncology Group performance status ≥2. The most common subtype was gall bladder cancer (GBC), seen in 94 patients (63.5%); 126 (85.1%) patients presented with de novo metastases. At a median follow-up of 6.8 months (95% CI, 5.9 to 7.8), the estimated mOS for the entire cohort was 12 months (95% CI, 7.8 to 16.3) and median progression-free survival was 8.2 months (95% CI, 7.1 to 9.4) with objective response achieved in 44 (29.7%) patients, and the estimated 2-year OS being 25%. Immune-related grade 3/4 adverse events were reported in 11 (7.4%) patients. In multivariate analysis, age <60 years (
P
= .001) and standard dose of durvalumab (
P
< .001) were found to have improved OS compared with age >60 years and low dose of durvalumab.

CONCLUSION

To our knowledge, these real-world data provide the first evidence in Indian context of the efficacy and safety of durvalumab plus chemotherapy in patients with advanced/metastatic BTCs especially in GBC.
Discovery of Gene Fusions in Driver-Negative Cancer Samples From the National Cancer Institute-Molecular Analysis for Therapy Choice Screening Cohort
Authors: Kaluziak Stefan T. , Codd Elizabeth M. , Purohit Rashi , Melli Beatrice , Kalyan Prinjali , Fordham Jo Anne , Kirkpatrick Grace , McShane Lisa M. , Chang Ting-Chia , Yang Guangxiao , Wang Jinglan , Williams P. Mickey , Karlovich Chris , Sklar Jeffrey , Iafrate A. John
Published: December 2024

PURPOSE

The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial was implemented to identify actionable genetic alterations across cancer types and enroll patients accordingly onto treatment arms, irrespective of tumor histology. Using multiplex polymerase chain reaction (PCR) next-generation sequencing, NCI-MATCH genotyped 5,540 patients, discovering gene fusions in 202/5,540 tumors (3.65%). This result, substantially lower than the fusion detection prevalence of 8.5% across all patients with cancer screened at Massachusetts General Hospital's (MGH) clinical laboratories, supported reanalysis of NCI-MATCH samples identified as mutations-of-interest (MOI)–negative. The assay used by NCI-MATCH requires previous knowledge of both fusion genes, cannot detect novel fusions, and may underestimate fusion-positive patients. Anchored multiplex PCR (AMP) technology permits fusion detection with knowledge of just one gene of the fusion partners.

METHODS

Using AMP-based kits, we reprocessed 663 MOI-negative samples. 200 ng of RNA per sample were shipped from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network biorepository to MGH (n = 319) and Yale University (n = 344), processed, and sequenced on the NextSeq550. Reported fusions were manually reviewed, and novel fusions orthogonally verified via reverse-transcription PCR and Sanger sequencing.

RESULTS

AMP identified 148 fusions in 142/663 MOI-negative patients (21% [95% CI, 18 to 25]), of which 28 were covered by the Oncomine Comprehensive Assay (OCA) panel but missed, while 120 were not covered by OCA. Among AMP-identified positive patients, 32 had actionable fusions, 24 contained novel fusions, and six had two fusion events. We identified fusions in 12/34 (35% [95% CI, 20 to 54]) cholangiocarcinomas and 43/109 (39% [95% CI, 30 to 49]) sarcomas.

CONCLUSION

Technology and awareness of actionable fusions have improved since the NCI-MATCH trial. With AMP-based technology, we identified 142 patients with fusions not detected during NCI-MATCH screening, many potentially actionable. These striking data underscore the need to optimize the fusion-detection capabilities of genotyping assays used in precision medicine.
Identification of a Suitable Subgroup for Radiation Dose Escalation in Definitive Concurrent Chemoradiation Therapy for Nonmetastatic Esophageal Squamous Cell Carcinoma
Authors: Shen Po-Chien , Chuang Wei-Kai , Dai Yang-Hong , Lo Cheng-Hsiang , Su Yu-Fu , Yang Jen-Fu , Huang Wen-Yen , Lin Chun-Shu , Lu Chia-Feng
Published: December 2024

PURPOSE

Dose escalation may only be suitable for some patients with esophageal cancer (EC) undergoing concurrent chemoradiotherapy (CCRT). This study aimed to identify specific subgroups of patients for whom dose escalation was most beneficial.

MATERIALS AND METHODS

Between January 2008 and December 2022, 187 patients with EC underwent CCRT; 94 patients received high-dose (HD) radiotherapy (RT; >64.8 Gy), and 93 patients received low-dose (LD) RT. We developed a model on the basis of clinical and radiomic features to compare the predicted survival probabilities of patients with EC receiving HD- and LD-RT. Patients suitable for HD-RT could be identified. We validated our findings of a suitable HD subgroup by evaluating the actual overall survival (OS) across different subgroups in the testing set.

RESULTS

Our model comprised HD and LD submodels, each predicting patient survival under their respective RT doses. The HD and LD submodels achieved concordance indexes of 0.78 and 0.75 in their respective testing sets. The average areas under the receiver operating characteristic curve over years 1-3 were 0.890 and 0.807 in the HD and LD testing sets, respectively. By comparing patients' predicted survival under HD- and LD-RT in the model, we classified the patients in the testing set into the HD-suitable (HDS) subgroup and the HD-unsuitable subgroup. In the subgroup analysis, HD-RT led to a better OS benefit for the identified HDS subgroup compared with LD-RT (
P
= .014). Among the HD-treated patients, the HDS subgroup showed better OS than did patients identified as unsuitable (
P
< .001).

CONCLUSION

We identified a suitable subgroup of patients with EC who might benefit from HD-RT. This model could aid clinicians in prescribing RT doses.
Latinx Cosmopolitanism in the Global South: Víctor Hernández Cruz and the Nostalgia of Egypt
Authors: Quesada Sarah M.
Published: December 2024

This essay addresses the undertheorized three-decade engagement of US Puerto Rican poet Víctor Hernández Cruz with North Africa. In his poems on Egypt, the author argues that Cruz’s particular brand of south–south engagement is excluded from cosmopolitan theory—one that tends to privilege either a Latin American elite or US American mobility. Yet Cruz’s nostalgia for Egyptian antiquity goes as far as to unsettle major conceptions of modernity, especially in his book of poems Beneath the Spanish (2017). By privileging North African epistemologies, Cruz’s poetry challenges the internalization of whiteness for a Latinx population. But part of the issues that arise with this valorization is that Cruz’s poetry draws from a Cold war-era nostalgia of internationalist (or “Nasserist”) rhetoric, and other forms of Egyptian neoliberal nationalisms that complicate Cruz’s particular brand of cosmopolitanism. Despite these complications, Cruz’s transatlantic engagement is distinct in its Global South formulations and expands notions of what it means to be a cosmopolitan in the twenty-first century.
“Une origine oubliée”: Global Modernity and East-West Debates over Classical Heritage
Authors: Johnson Ryan
Published: December 2024

Analogies between the ancient Mediterranean and premodern China and Japan are a well-noted phenomenon in literary studies. Recently, a wealth of scholarship has reignited interest in how people from either side of the Eurasian continent sought to understand one another through comparisons between an imagined shared antiquity. Yet less work has been done comparing Eastern and Western ways of conceiving this analogy with current work in comparative literature. This essay considers late nineteenth- through early twentieth-century East Asian and Western analogies between classical East Asian and ancient Mediterranean cultures. Looking at examples from literature, philosophy, and fine art, it shows that making analogies between classical Chinese and Japanese cultures and ancient Greece and Rome was a shared strategy among prominent European and East Asian figures seeking to renew national traditions by reimagining the origins of both “East” and “West.” However fantastical, these imagined shared histories, seen in the work of Ernest Fenollosa, Watsuji Testurō, W. B. Yeats, and Kuki Shūzō, are an important point of contact between the conceptual foundations of East Asian and Western modernities, and an important element of the study of modernism itself.
Translation and Polylanguaging: Sexuality and Novels from James Baldwin to Mohamed Mbougar Sarr
Authors: Lucey Michael
Published: December 2024

This article examines some conceptual and methodological issues that come up when approaching transcultural relations between sexuality and language in the contemporary world. Most of the examples come from novels. Language about sexuality is often filled with implicitness. To put it differently, it is highly indexical language. This poses problems both for understanding and for translation. How do you talk about sexuality when talking about different times and places in which different languages are spoken and different implicit structures of cultural concepts produce the social forms within which sex/gender and sexuality take place? Added to this is the problem of the coexistence of multiple sexual ideologies and sexual cultures, as well as of multiple languages, in the same social space. “Given that the novel is a fundamentally monolingual form,” Amitav Ghosh has written, “how does it deal with characters whose linguistic identities are complex and unsettled?” In this article, the author examines novelistic situations in which both linguistic and sexual identities are “complex and unsettled.” What are the limits of translation in such situations? What kind of linguistic anthropological work can novels do? Literary examples are drawn from works by James Baldwin, Tahar Ben Jelloun, Abdellah Taïa, and Mohamed Mbougar Sarr.
The Hikayat Abdullah, the Missionary Press, and the Making of Nineteenth-Century “World Literature”
Authors: Werner Winter Jade
Published: December 2024

According to many British Orientalists, Malay was decidedly inferior to Sanskrit or Arabic. This essay examines Abdullah bin Abdul Kadir’s efforts to counter the second-rate status accorded to Malay literature in his autobiography, the Hikayat Abdullah (1849). The text represents an attempt to present Malay writing to European audiences as a coherent national and, by extrapolation, world literature. Retracing Abdullah’s strategic textual work is important not only because it helps explain his status as the “Father of Modern Malay Literature,” but also because it exposes the processes contributing to the construction of nineteenth-century world literature. In its critique of and appeal to Euro-American readers, the Hikayat Abdullah illustrates the degree to which world literature depended on imperial preoccupations with “nationness,” which meant that debates over the “world” status of non-Western texts often played out in colonial microencounters rather than European metropoles. Moreover, Abdullah’s text demonstrates how the secular logics undergirding world literature were significantly produced by missionary institutions, given their involvement in colonial publishing. Contextualizing the Hikayat Abdullah and the broader concept of world literature in this imperial frame, this essay develops a literary microhistory to illumine the criteria to which non-Western texts conformed in order to be regarded as properly “literary.”
The Changing Identities of American Wives and Mothers
Authors: Lafortune Jeanne , Salisbury Laura , Siow Aloysius
Published: December 2024

Over the last century, resource allocations within families changed significantly, as did marriage matching patterns. College-educated women became more likely to marry (and, to a lesser extent, have children) than less educated women. A large literature documents these patterns and proposes a variety of explanations. We review this literature. Then, we provide a unified empirical framework, which can integrate these mechanisms. We demonstrate the usefulness of that framework by employing it in decennial US censuses and showing that a combination of technological changes that increased the value of children’s education and enabled more educated women to devote more time to child-rearing are consistent with multiple behavioral changes within marriage, on the marriage market, and before marriage. (JEL I20, J12, J13, J16, N31, N32)
How Sanctions Work: Iran and the Impact of Economic Warfare
Authors: Elliott Kimberly Ann
Published: December 2024

Kimberly Ann Elliott of Former Senior Fellow with the Peterson Institute and the Center for Global Development reviews “How Sanctions Work: Iran and the Impact of Economic Warfare” by Narges Bajoghli, Vali Nasr, Djavad Salehi-Isfahani, and Ali Vaez. The Econlit abstract of this book begins: “Explores how sanctions have impacted the political calculus of those in power in Iran, providing a fuller picture of how prolonged comprehensive sanctions both impact the targeted society and reverberate outward into international politics and economics.”
Taming the Street: The Old Guard, the New Deal, and FDR's Fight to Regulate American Capitalism
Authors: Fohlin Caroline
Published: December 2024

Caroline Fohlin of Emory University reviews “Taming the Street: The Old Guard, the New Deal, and FDR's Fight to Regulate American Capitalism” by Diana B. Henriques. The Econlit abstract of this book begins: “Explores Franklin Delano Roosevelt's development and enactment of the New Deal after the 1929 stock market crash and subsequent Great Depression, focusing on the establishment of the Securities and Exchange Commission (SEC).”
Σχεδίαση βρόχου κλειδωμένης φάσης για εφαρμογές χαμηλής ισχύος
Authors: Σαμαράς Δημήτριος
Published: December 2024

Την τελευταία δεκαετία γινόμαστε όλοι μάρτυρες της ραγδαίας εξέλιξης των ημιαγωγών. Από το 2012 όπου το μήκος καναλιού των τρανζίστορς στη βιομηχανική παραγωγή ήταν 22nm, σήμερα, το 2023, κρατάμε στο χέρι μας συσκευές που περιλαμβάνουν τρανζίστορς με μήκος καναλιού 3nm. Μάλιστα, το 2024 προβλέπεται να κατασκευαστεί το πρώτο ολοκληρωμένο κύκλωμα που θα περιλαμβάνει τρανζίστορς με μήκος καναλιού 2nm. Φυσικά, το κίνητρο για τη συνεχή μείωση του μήκους καναλιού, εντοπίζεται στο κέρδος ταχύτητας, κατανάλωσης και εμβαδού ωφέλιμου πυριτίου. Οι ηλεκτρονικές συσκευές καθημερινής, και όχι μόνο, χρήσης γίνονται όλο και μικρότερες, γρηγορότερες και καταναλώνουν λιγότερη ηλεκτρική ενέργεια, κάτι το οποίο τα τελευταία χρόνια βρίσκεται δικαιολογημένα στο επίκεντρο συζητήσεων λόγω τις κλιματικής αλλαγής. Εντός των περισσότερων ολοκληρωμένων κυκλωμάτων που αναφέρθηκαν παραπάνω θα βρει κάποιος πολλά κυκλώματα όπως ενεργά και παθητικά φίλτρα, ενισχυτές χαμηλού θορύβου (Low Noise Amplifiers, LNAs), ενισχυτές ισχύος (Power amplifiers, PAs), ανορθωτές κρυστάλλων, ανιχνευτές ισχύος (TSSI, RSSI), μετατροπείς αναλογικού σε ψηφιακό σήμα και αντίστροφα και άλλα. Είτε συζητάμε για κυκλώματα ασύρματης ή ενσύρματης μεταφοράς πληροφορίας, σχεδόν όλα περιλαμβάνουν έναν συνθέτη συχνότητας (frequency synthesizer), ο οποίος είναι υπεύθυνος για την δημιουργία μίας ή πολλών συχνοτήτων. Στη βιβλιογραφία αλλά και στη βιομηχανία υπάρχουν αρκετοί συνθέτες συχνότητας, ωστόσο, ο βρόχος κλειδωμένης φάσης (Phased-locked loop, PLL) έχει κυριαρχήσει λόγω των πολλών πλεονεκτημάτων που παρουσιάζει έναντι των λοιπών λύσεων. Η παρούσα διατριβή παρουσιάζει τη σχεδίαση σε σχηματικό και φυσικό σχέδιο ενός βρόχου κλειδωμένης φάσης με τα κυριότερα χαρακτηριστικά του τον χαμηλό θόρυβο, την χαμηλή κατανάλωση και το εξαιρετικά μικρό εμβαδό πυριτίου.
Trigeminal Neuralgia - Impact on Daily Activities and Sports, Treatment Options That Enable a Pain-Free Life
Authors: Kisiel-Cybula Ewelina , Sionek-Wręga Irena , Jakubowska Eliza , Ślemp Julia , Pakuła Anita , Kuźma Krzysztof , Bierć Karolina , Grochowska Marcelina , Hoppe-Mitera Ewa , Wręga Jakub
Published: December 2024

The review highlights that TN has a prevalence of 0.16%–0.3%, predominantly affecting women, with an increased incidence among individuals over 50 years of age. TN etiology includes neurovascular compression, demyelinating conditions like multiple sclerosis, and familial genetic predispositions. Classification systems, such as the 2018 ICHD-3, provide diagnostic criteria and categorize TN into classical, secondary, and idiopathic types. First-line treatments involve antiepileptic medications such as carbamazepine and oxcarbazepine, with second-line options including lamotrigine and baclofen. For refractory cases, microvascular decompression and percutaneous techniques are recommended, with options like gamma knife radiosurgery (GKRS) and botulinum toxin injections showing promise. Despite available treatments, TN’s recurrent nature underscores the need for personalized, multidisciplinary management to address both physiological and mental health impacts.
Efecto de la temperatura en la morbilidad diaria por influenza-neumonía en menores de cinco años en Medellín (Colombia)
Authors: Romero Hereira Jhon Mario , Restrepo Lopera Ana Maria , Grisales Romero Hugo de Jesús
Published: December 2024

Introducción. Los cambios en la temperatura perjudican el sistema inmunitario y favorecen la aparición de enfermedades respiratorias. El objetivo de esta investigación es determinar el efecto de la temperatura en la influenza y neumonía según factores meteorológicos y ambientales, en los menores de cinco años de la ciudad de Medellín, Colombia. Materiales y métodos. Estudio ecológico de series de tiempo con fuentes de información secundaria. Se construyeron Modelos Aditivos Generalizados, con función de enlace Poisson para determinar la oportunidad de enfermar por influenza y neumonía con las técnicas de rezagos distribuidos, para incrementos en la temperatura. Resultados. Cuando se ajustó por factores meteorológicos y ambientales, la temperatura se asoció significativamente con los casos diarios de influenza y neumonía: incremento del 8.0% el día de la exposición por cada aumento de 1°C y del 50.0% si el incremento fuese de 5°C. Discusión. Retrasos cortos hasta de 0 a 3 días permiten modelar la significación de las altas temperaturas y retrasos largos tienen efectos significativos a bajas temperaturas, para determinar la oportunidad de enfermar por influenza-neumonía. Conclusión. Cuantificar el efecto de la temperatura, sobre la influenza y neumonía es crucial para el desarrollo de estrategias sanitarias.
Palabras clave: contaminación ambiental, cambio climático, temperatura