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Nanoparticle (NP)-based drug delivery systems are promising in anticancer therapy, capable of delivering cargo with superior selectivity and achieving enhanced tumor accumulation compared to small-molecule therapeutics. As more efforts are being devoted to NP development, molecular polymer bottlebrushes (MPBs) have gained attention as a potential drug delivery vehicle. To date, the influence of various MPB parameters such as size, shape, and surface charge in determining tumor penetrability have been systematically probed. However, the role of amphiphilicity, specifically the hydrophilic-hydrophobic balance, remains unexplored. In this study, a series of MPBs are employed with varied hydrophobicity levels to reveal a dependence between MPB composition, cell association, and tumor homing. The data indicates that increasing levels of hydrophobicity in MPBs (to a certain level) demonstrate only marginal effects in vitro but reveals enhanced tumor homing in a mouse model of ovarian cancer in vivo, where more hydrophilic MPBs exhibit low tissue deposition and low tumor homing. In contrast, more hydrophobic MPBs show significant tumor accumulation and homing due to their engineered hydrophobicity.

Abstract The nomenclature high-grade non-Hodgkin's lymphoma was repurposed in the World Health Organization (WHO) 2016 update as high-grade B cell lymphoma (HGBL). However, among the HGBL entities HGBL, not otherwise specified (NOS) remains a poorly described entity with a lack of literature regarding its treatment and prognosis. The baseline characteristics, treatment, and outcome of HGBL, NOS cases were analyzed. Thirty HGBL, NOS patients were diagnosed between January 2017 and December 2019. Their median age was 49.3 years, and 30% had advanced IPI. The majority received R-CHOP chemotherapy, while five patients received dose-adjusted R-EPOCH. At a median follow-up of 15 months, nine patients had disease progression or relapse. EFS and OS were 22 months (12.1–31.9 months) and 37 months (29.4–44.0 months) respectively. Only NCCN-IPI ≤ 2 showed significant influence on the outcome. The results were similar to the outcomes previously reported. This study highlights the importance of NCCN-IPI in ascertaining the prognosis of HGBL, NOS. The literature review suggests that more intensive chemotherapy is ideal for HGBL, NOS. However, prospective trials are needed to prove whether the treatment of HGBL, NOS can be tailored based on NCCN-IPI.

Introduction: Anuradhapura is located in the North Central province of Sri Lanka which is about 200 kilometres away from Colombo which is the commercial capital of Sri Lanka. About 22 to 25 arterial repairs are done for major limb vessel injuries (popliteal, femoral, iliac, brachial, axillary and subclavian arteries) for 1 year at The Anuradhapura Teaching Hospital. Common causes for major lower Limb arterial injuries include Road Traffic Accidents (RTA) and Trap Guns. Trap Gun is an improvised illegal device used to protect crops from animals in Sri Lanka. This is very prevalent in North Central province of Sri Lanka where the Teaching Hospital Anuradhapura is located. Materials and Methods: This study is a retrospective case note based study reporting the outcome of patients presenting with major lower Limb arterial injuries to the Teaching Hospital Anuradhapura including the injuries caused by the trap gun. Results: 24 patients were included with major lower limb arterial injury following trauma. 8 (33.3%) injuries were following trap gun. Two patients following trap gun injury underwent amputation whereas no one underwent amputation when the cause of injury was other than trap gun. This difference in outcome was significant (P 0.0277). Conclusions: Therefore trap gun injury results in poor outcome probably due to associated severe soft issue injury and contamination.

Lateral Medullary Syndrome (LMS) is a well-documented vascular syndrome of the posterior circulation territory. This syndrome is easily localised because of characteristic presentation, unique territory of blood supply and very small area of involvement. We present a case of Wallenberg’s syndrome which did not have all the classical components of the syndrome, like Horner’s syndrome. Opalski syndrome is a rare variant of Wallenberg syndrome, where lateral medullary syndrome is associated with ipsilateral hemiparesis. This case report highlights how differential involvement of the lateral part of medulla can result in varied presentation.

Seat belt syndrome is associated with multiple visceral injuries and vertebral burst fractures. Small Intestinal perforations are seen in 5–15 % of blunt abdominal trauma. In our case, we will report a case that presented small intestinal perforation and thoracic vertebral fracture caused by a different mechanism. Previously healthy 48-year-old male presented to the emergency department following falling from 15 feats height. He was a paraplegic with a sensory level at T12. He did not have a clinical feature of spinal shock. He was complaining of epigastric and central abdominal pain and tenderness and was diagnosed to have a proximal Jejunal perforation associated with an unstable fracture of T12 causing spinal compression. Open intestinal repair followed by a posterior spinal exploration and pedicle screw fixation done. Violent injury due to different mechanisms can have similar injuries to Seat belt syndrome. Ultrasonography is used to detect pneumoperitoneum, but the Contrast study is the gold standard to detect visceral injuries. The surgical approach to visceral injury depends on the patient's condition. But the laparoscopic approach has a more favorable postoperative outcome than open access. Intestinal perforations associated with the neurological deficit are difficult to identify in an initial clinical assessment. Thoracolumbar fractures can associate with small bowel injuries during high-velocity trauma. Early identification and repair of the intestinal injury are important to prevent devastating complications and to improve neurological recovery after spinal surgery. • Seat belt syndrome is associated with a characteristic set of visceral injuries and spinal fractures. • Violent injuries caused by a different mechanism can cause similar injuries to Seat belt syndrome. • Thorough clinical examination with ultrasonography and contrast studies helps to detect visceral injuries. [ABSTRACT FROM AUTHOR]

The traumatic diaphragmatic hernia could be missed in the background of spinal fractures due to neurological weakness. We report the first case of the management of thoracolumbar fracture-dislocation associated with diaphragmatic injury. 53-year-old male transferred from local hospital following fallen from a motorbike on the 4th day after the injury. He was paraplegic from L1 below with sacral root involvement. Further imaging showed fracture-dislocation of the vertebral body at the T12-L1 level and anterior displacement of T11 on T12. The left-sided diaphragmatic hernia was detected by chest x-ray with bowel shadows in the left hemithorax. Emergency laparotomy and diaphragmatic repair followed by a posterior spinal exploration and pedicle screw fixation were done. Early mobilization was done after spinal fixation and the patient is successfully continuing rehabilitation. Thoracolumbar fracture-dislocation associated with the traumatic diaphragmatic hernia is rare. Clinical diagnosis of associated visceral injuries could be delayed due to the neurological deficit of the patient. An initial concern was to repair the life-threatening diaphragmatic hernia. Even current studies showed improved neurological function from early spinal surgery, spinal fixation had to delay as surgery needs a prone position. Early identification and management of traumatic diaphragmatic hernia are life-saving and allows early surgical intervention for the spine. Early reduction and fixation are associated with improved neurological function and will allow early mobilization and reduce hospital and ICU stay. • Traumatic Diaphragmatic hernia is a life-threatening condition which may not presented with classical features in the presence of spinal cord injury. • Careful clinical and radiological assessment is necessary to detect this condition in the presence of neurological weakness. [ABSTRACT FROM AUTHOR]

Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8 + T cell responses via dysregulation of calcium efflux., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute Promyelocytic Leukemia (APL) is associated with excellent long-term outcomes. However, early mortality due to coagulopathy remains a challenge. In this study we examined the bleeding and thrombotic manifestations, as well as incidence of Early Death secondary to thrombosis/hemorrhage (ED-TH) in patients with APL. Early death (ED) was defined as death occurring within 30 days of induction therapy. Two-hundred forty-eight patients were included in the study. Overall, 57 patients had evidence of a major bleed/thrombosis at presentation or during induction therapy, including 44 patients with a major bleed, 8 patients with thrombosis and 5 patients with both evidence of thrombosis and a major bleed. Forty patients (16.1%) had ED, of which 21 had ED-TH. The cumulative incidence of death due to thrombo-hemorrhagic complications at 30 days was 8.4%. On univariate analysis, increasing Prothrombin time (PT)(p-<0.001), white blood cell count (p < 0.001) and activated Partial thromboplastin time (aPTT) (p < 0.001) were statistically significantly associated with increased risk of ED-TH. However, on multivariate analysis, only increasing PT (p-0.025) and aPTT (p-0.041) were significantly associated with increased risk of ED-TH., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Intraepithelial lymphocytes (IELs), including αβ and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/ TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.

A series of ethylene glycol-based squaramide-containing copolymers are synthesized via a post-polymerization functionalization strategy. Conversion of polymeric amines to squaramides is found to proceed in good yields, representing a versatile method of incorporating squaramides into polymers for anion recognition. Analysis of the polymers by UV-Vis and fluorescence spectroscopy revealed that anion binding takes place similarly to that of small-molecule squaramides. The presence of a fluorescent sensing group on polymer-bound squaramides allowed for a fluorescent sensing mechanism for anions that followed a similar trend in selectivity in aqueous DMSO solution, with selectivity observed for H 2 PO 4 - , AcO - and SO 4 2- over other common anions tested. The anion response and selectivity towards anions is similar to that of analogous small-molecule squaramides, however polymeric squaramides exhibited a greater resistance to deprotonation by more basic anions, which is attributed to the closer proximity of individual squaramides on a macromolecule. The squaramide-containing polymers exhibited good water solubility, overcoming a common problem for anion sensors which are typically not sufficiently soluble in water to function in many required applications. Despite no anion binding being observed in water, this study represents a simple and effective method of creating fully water-soluble anion receptors which may be adapted to give improved binding affinity and selectivity depending on the anion binding moiety., (© 2023 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)

Background: Several studies have demonstrated the analytical sensitivity of MALDI-TOF mass spectrometry (MALDI-TOF MS) by immunoenrichment for M-protein analysis. We report the results of a novel, low-cost, reagent-based extraction process using acetonitrile (ACN) precipitation to enrich for κ and λ light chains which can be analysed by MALDI-TOF MS., Methods: Institutional Ethics committee approval was obtained. Serum samples from patients with monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), plasmacytoma, AL amyloidosis and Waldenström macroglobulinemia (WM) underwent ACN precipitation. The images obtained were overlaid on apparently healthy donor serum samples to confirm the presence of M-protein. A sample was considered positive for M-protein if there was a sharp or broad peak within the κ or λ mass/charge ( m/z) range: m/z- [M + 2H] 2+ : 11,550-12,300 Da and λ m/z - [M + 2H] 2+ : 11,100-11,500 Da. Images were acquired at a m/z range of 10,000-29,000 Da. Corresponding serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (IFE) and serum free light chain (sFLC) assay by nephelometry were performed for all the samples., Results: Two-hundred-and-two serum samples were included in the study: MM- 184 (91%); AL amyloidosis- 2 (1%); plasmacytoma- 8 (4%); MGUS- 6 (3%) and WM- 2 (1%). All the SPEP positive samples were identified by MALDI-TOF MS. Out of 179 samples positive for M-protein by IFE, MALDI-TOF MS was positive in 176 samples (98%). Compared to IFE, the sensitivity and specificity of M-protein identification by MALDI-TOF MS were 98.3% and 52.2%, respectively., Conclusions: This study demonstrates the feasibility of qualitatively identifying M-protein without the need for antibody-based immunoenrichment, making the technique cost-effective., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GG, NM, SJ, Indian provisional patent application no: 202041009443, filed on 5 March 2020.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high-risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate- and high-risk disease received a further 2 years of maintenance with ATRA, 6-mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow-up. The mean (SD) estimated 5-year event-free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5-year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Infants and young children receive the highest exposures to antibiotics globally. Although there is building evidence that early life exposure to antibiotics increases susceptibility to various diseases including gut disorders later in life, the lasting impact of early life antibiotics on the physiology of the gut and its enteric nervous system (ENS) remains unclear. We treated neonatal mice with the antibiotic vancomycin during their first 10 postnatal days, then examined potential lasting effects of the antibiotic treatment on their colons during young adulthood (6 weeks old). We found that neonatal vancomycin treatment disrupted the gut functions of young adult female and male mice differently. Antibiotic-exposed females had significantly longer whole gut transit while antibiotic-treated males had significantly lower faecal weights compared to controls. Both male and female antibiotic-treated mice had greater percentages of faecal water content. Neonatal vancomycin treatment also had sexually dimorphic impacts on the neurochemistry and Ca 2+ activity of young adult myenteric and submucosal neurons. Myenteric neurons of male mice were more disrupted than those of females, while opposing changes in submucosal neurons were seen in each sex. Neonatal vancomycin also induced sustained changes in colonic microbiota and lasting depletion of mucosal serotonin (5-HT) levels. Antibiotic impacts on microbiota and mucosal 5-HT were not sex-dependent, but we propose that the responses of the host to these changes are sex-specific. This first demonstration of long-term impacts of neonatal antibiotics on the ENS, gut microbiota and mucosal 5-HT has important implications for gut function and other physiological systems of the host. KEY POINTS: Early life exposure to antibiotics can increase susceptibility to diseases including functional gastrointestinal (GI) disorders later in life. Yet, the lasting impact of this common therapy on the gut and its enteric nervous system (ENS) remains unclear. We investigated the long-term impact of neonatal antibiotic treatment by treating mice with the antibiotic vancomycin during their neonatal period, then examining their colons during young adulthood. Adolescent female mice given neonatal vancomycin treatment had significantly longer whole gut transit times, while adolescent male and female mice treated with neonatal antibiotics had significantly wetter stools. Effects of neonatal vancomycin treatment on the neurochemistry and Ca 2+ activity of myenteric and submucosal neurons were sexually dimorphic. Neonatal vancomycin also had lasting effects on the colonic microbiome and mucosal serotonin biosynthesis that were not sex-dependent. Different male and female responses to antibiotic-induced disruptions of the ENS, microbiota and mucosal serotonin biosynthesis can lead to sex-specific impacts on gut function., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: T-lymphoblastic leukemia (T-ALL) patients expressing myeloid/stem cell antigens are classified as early T-cell precursor lymphoblastic leukemia (ETP-ALL) or near-ETP-ALL., Methods: Clinico-laboratory profiles, flow cytometric end-of-induction measurable residual disease (EOI-MRD), and survival of treatment naïve T-ALL patients were analyzed according to their immunophenotypic subtypes., Results: Among 81 consecutive T-ALL patients diagnosed, 21% (N=17) were ETP-ALL and 19% (N=15) were near-ETP-ALL. EOI-MRD was detectable in 39% of the 59 samples tested (31.6% of pediatric samples and 52.4% of adult samples). The frequency of EOI-MRD positivity was significantly higher among ETP-ALL (75%, P =0.001) and near-ETP-ALL (71%, P =0.009) patients compared to that in conventional-T-ALL (con-T-ALL) patients (22.5%). CD8 (P=0.046) and CD38 (P=0.046) expressions were significantly upregulated in the EOI blasts of con-T-ALL and ETP-ALL samples, respectively. The 2-year rates of overall (OS), relapse-free (RFS), and event-free survival (EFS) among the T-ALL patients (pediatric vs. adult) was 79.5% vs. 39.8% ( P <0.001), 84.3% vs. 60.4% ( P =0.026), and 80.3% vs. 38% ( P <0.001), respectively. Univariate analysis revealed that 2-year EFS and RFS of pediatric T-ALL patients was independent of T-ALL subtype and was influenced only by EOI-MRD status. However, 2-year OS, RFS, and EFS among adult T-ALL patients were EOI-MRD independent and influenced only by the near-ETP-ALL phenotype., Conclusion: Two-year survival among pediatric and adult T-ALL patients is attributed to EOI-MRD status and near-ETP-ALL phenotype, respectively.