Treatment Window Research Articles

IMMU-16. ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY

Abstract Immunotherapy trials in glioblastoma patients increasingly avoid immunosuppressive steroids and consider bevacizumab as alternative anti-edema treatment. Since VEGF is also a potent immunosuppressive factor, we explored the dimension and mechanisms of immune-mediated effects of anti-VEGF treatment. Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout mice and animals were treated with B20 (anti-murine VEGF) or dexamethasone. Immune cells were profiled by flow cytometry, and RNAseq was performed on sorted tumor and immune cells at different timepoints. B20 prolonged the survival of immunocompetent mice but not of Pfp/Rag2 knockout mice, indicating that the immune system is essential for its effect. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vascularization, whereas B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and α/β TCR genes. The proportion of progenitor-like exhausted CD8+ cells, which are responsive to PD-1 blockade, was increased in B20-ea. In CD4+ cells, B20 caused skewing towards TFH, while dexamethasone increased TH2 cytokine expression. Depletion experiments demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of B20. To conclude, anti-VEGF therapy has significant immunostimulatory effects which are, however, largely transient, so that an early treatment window of opportunity may exist during which it could actively support immunotherapy.

Profiles of Nonpharmacologic Treatment Receipt in the First 10 Weeks Following a New Back Pain Diagnosis Among Active Duty Soldiers: A Latent Class Analysis.

US service members experience high rates of back pain. Guidelines prioritize nonpharmacologic treatment (NPT) as first-line pain treatments; however, NPT utilization patterns research is limited. This study examined NPT patterns of care within the first 10 weeks following an index back pain diagnosis. Data were from the Substance Use and Psychological Injury Combat Study and included 222,427 active duty soldiers with an index back pain diagnosis following return from Afghanistan/Iraq deployment in 2008-2014. We fit a series of latent class analysis models to identify homogenous subgroups of soldiers with NPT utilization during the 10-week period and measured associations with soldier characteristics and clinical characteristics within 90 days before the back pain diagnosis, with the distinct NPT utilization classes. Approval for this study was granted by the Brandeis University Committee for Protection of Human Subjects (Institutional Review Board #14153) and the Uniformed Services University Institutional Review Board. Only half of the soldiers received any NPT within their 10-week early treatment window. Latent class analysis identified 4 classes over the 10-week early treatment window: Class 1 (None/Low NPT, 65%); Class 2 (High and Decreasing NPT, 15%); Class 3 (Low and Increasing NPT, 13%), and Class 4 (Sustained NPT, 7%). Soldier clinical characteristics from the 90-day preperiod window were most important in distinguishing class membership in relation to Class 1, particularly comorbid pain conditions, diagnosis of traumatic brain injury, receipt of prescription opioids, and receipt of invasive surgery. Patterns of weekly NPT utilization during an early treatment window following a new back pain diagnosis varied temporally, with approximately half of soldiers using NPT. Half of the soldiers did not receive any NPT within their 10-week early treatment window, which highlights opportunities for increasing use of NPT utilization among military members with a new back pain episode. Future research is needed in the Military Health System to examine the extent to which NPT patterns are associated with pain management outcomes.

SDS-Net: A Synchronized Dual-Stage Network for Predicting Patients Within 4.5-h Thrombolytic Treatment Window Using MRI.

Timely and precise identification of acute ischemic stroke (AIS) within 4.5h is imperative for effective treatment decision-making. This study aims to construct a novel network that utilizes limited datasets to recognize AIS patients within this critical window. We conducted a retrospective analysis of 265 AIS patients who underwent both fluid attenuation inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) within 24h of symptom onset. Patients were categorized based on the time since stroke onset (TSS) into two groups: TSS ≤ 4.5 h and TSS > 4.5 h. The TSS was calculated as the time from stroke onset to MRI completion. We proposed a synchronized dual-stage network (SDS-Net) and a sequential dual-stage network (Dual-stage Net), which were comprised of infarct voxel identification and TSS classification stages. The models were trained on 181 patients and validated on an independent external cohort of 84 patients using metrics of area under the curve (AUC), sensitivity, specificity, and accuracy. A DeLong test was used to statistically compare the performance of the two models. SDS-Net achieved an accuracy of 0.844 with an AUC of 0.914 in the validation dataset, outperforming the Dual-stage Net, which had an accuracy of 0.822 and an AUC of 0.846. In the external test dataset, SDS-Net further demonstrated superior performance with an accuracy of 0.800 and an AUC of 0.879, compared to the accuracy of 0.694 and AUC of 0.744 of Dual-stage Net (P = 0.049). SDS-Net is a robust and reliable tool for identifying AIS patients within a 4.5-h treatment window using MRI. This model can assist clinicians in making timely treatment decisions, potentially improving patient outcomes.

Curcumin’s Radioprotective Effects on Zebrafish Embryos

Radiation modifiers are largely studied for their contribution to enlarging the treatment window. Curcumin is already known for its antioxidant properties; however, its role as a radioprotector in preclinical studies is affected by the well-known low absorption and bioavailability of curcumin. In this study, curcumin’s radioprotection ability has been evaluated in zebrafish larvae, by taking advantage of quantifying curcumin absorption and evaluating its fluorescence in transparent embryos. A curcumin range of 1–10 μM was tested to select the non-toxic concentrations to be used for a pre-treatment of photon beam irradiation using a 2–15 Gy range of doses. The post-treatment analysis within 120 h post-fertilization (hpf) included an assessment of mortality and malformation rates and behavioral and gene expression analysis. A total of 2.5 and 5 μM of curcumin pre-treatment showed a radioprotective role, significantly reducing the frequency of embryo malformations and damaged entities. This sparing effect disappeared using 15 Gy, showing the radiation effect’s prevalence. Gene expression analysis reconducted this radioprotective ability for antioxidant gene network activation. The curcumin-induced activation of the antioxidant gene network promoted radioprotection in zebrafish.

NIR-II Fluorescent Nanotheranostics with a Switchable Irradiation Mode for Immunogenic Sonodynamic Therapy.

Nanotheranostics, which integrate diagnostic and therapeutic functionalities, offer significant potential for tumor treatment. However, current nanotheranostic systems typically involve multiple molecules, each providing a singular diagnostic or therapeutic function, leading to challenges such as complex structural composition, poor targeting efficiency, lack of spatiotemporal control, and dependence on a single therapeutic modality. This study introduces NPRBOXA, a nanoparticle functionalized with surface-bound cRGD for targeted delivery to αvβ3/αvβ5 receptors on tumor cells, achieving theranostic integration by sequentially switching its irradiation modes. Under 808nm laser irradiation, NPRBOXA emits NIR-II fluorescence, which aids in identifying the nanoparticle's location and fluorescence intensity, thereby determining the optimal treatment window. Following this, the irradiation mode switches to ultrasound irradiation at the optimal treatment window. Ultrasound irradiation induces NPRBOXA to generate reactive oxygen species, promoting the reduction of OXA-IV to OXA-II, which in turn triggers immunogenic cell death. This mechanism enables a combination of sonodynamic therapy, chemotherapy, and immunotherapy for tumor treatment. The versatile design of NPRBOXA holds promise for advancing precision oncology through enhanced therapeutic efficacy and real-time imaging guidance.

Use of prototype bi-nasal prongs for noninvasive ventilation in foals.

Noninvasive ventilation (NIV) provides effective respiratory support in foals, but face masks are poorly tolerated and associated with hypercapnia. Bi-nasal prongs might be a more effective device interface in foals. To compare bi-nasal prongs and masks for NIV in foals with pharmacologically induced respiratory insufficiency. Six healthy foals. In a randomized cross-over study, sedated foals received NIV delivered by mask or bi-nasal prongs, with the treatment repeated using the alternative device interface after a 3-day rest period. After periods of spontaneous ventilation through the allocated interface, with and without supplementary O2 (T2-T3), foals were subject to 10-minute treatment periods of NIV at different pressure support (5 or 10 cmH2O) and end-expiratory pressure settings (5 or 10 cmH2O), with and without supplementary O2 (T4-T7). Vital signs, arterial blood gases, spirometry, and gas exchange data were measured in the final 2 minutes of each treatment window. Bi-nasal prongs were well tolerated and required less manual positioning or monitoring compared to the mask. Partial pressure of carbon dioxide did not increase during NIV with bi-nasal prongs and was lower than observed with masks (mean difference, 8.2 mmHg [95% confidence interval, 4.1-12.2 mmHg] at T6). Oxygenation and respiratory mechanics were improved in all foals and not different between device interfaces. Nasal prongs were well tolerated, had similar effects on respiratory function, and appeared to ameliorate hypercapnia observed previously during NIV in foals.

The Changing Landscape of Intravenous Thrombolysis for Acute Ischaemic Stroke

Intravenous thrombolysis remains the most accessible and effective reperfusion therapy available to patients with acute ischaemic stroke. Treatment with intravenous thrombolysis improves the odds of favourable functional outcome with the unacceptably low risk of haemorrhagic complications. Even in the current era of endovascular thrombectomy, intravenous thrombolysis remains the backbone of acute stroke treatment due to its accessibility and relative ease of administration. Since intravenous alteplase was first approved for acute ischaemic stroke in the mid 1990s, there have been significant advances in expanding the indication and time window for treatment, in addition to transitioning towards tenecteplase use for stroke thrombolysis. In this review, we will provide a narrative on the use of thrombolysis in acute ischaemic stroke including an up-to-date discussion on recent advances in thrombolytic therapy.

From onset to blindness: a comprehensive analysis of RPGR-associated X-linked retinopathy in a large cohort in China

BackgroundVariants in the RPGR are the leading cause of X-linked retinopathies (XLRPs). Further in-depth investigation is needed to understand the natural history.MethodsReview of all case records, molecular genetic testing results,...

Subcutaneous Granuloma Annulare: A Systematic Review on Current Treatments

Subcutaneous Granuloma Annulare (SGA) is a rare subset of Granuloma Annulare (GA), presenting most often in female children and young adults as a benign, nodular lesion. Etiology is unknown but can be linked to stress, immunologic disorders, connective tissue diseases and diabetes. We searched Scopus, PubMed, Embase, and OVID Medline to assess the current landscape of SGA treatment. We searched (“subcutaneous granuloma annulare” OR “pseudorheumatoid nodules” OR “deep granuloma annulare” OR “palisading granuloma”) AND (“treatment” OR “topical” or “injection”). Articles were limited to English language and human subjects. 302 unique studies were screened and assessed for eligibility by two reviewers working independently with disagreements resolved by a third reviewer’s decision. 33 articles met inclusion comprising case reports (n=27), case series (n=3) and retrospective case reviews (n=3) with a total of 149 patients involved. The most predominant treatment was surgical excision/biopsy (n=112) followed by steroid injection (n=6), topical steroid (n=5), and topical antibiotic (n=3). Reports of one patient responding to treatment (n=1) were reported for local hyperthermia, hydroxychloroquine, cyclophosphamide, oral isotretinoin, PUVA light therapy, and pentoxifylline. Of patients studied in these cases, 17 had spontaneous resolution of their lesions either after the treatment window or before starting treatment. One patient was refractory to targeted treatment but had resolution after achieving diabetic control. While surgical excision predominated, biopsy is standard for diagnosis but follow up was not consistent to assess recurrence. Our review calls for more trials and treatment options for SGA.

Defining the Treatment Window: Early Versus Late Pulsed Dye Laser Therapy for Posttraumatic and Surgical Scars in Asian Patients

ABSTRACTObjectivesThis retrospective study evaluates the effectiveness of pulsed dye laser (PDL) treatment in early versus late treatment groups for traumatic or postoperative scars. The study aims to determine the threshold between early and late treatment. Additionally, it investigates factors that may influence wound healing outcomes.MethodsThe medical records of 147 patients who underwent PDL treatment at our institution between January 2018 and December 2022 were retrospectively reviewed. Inclusion criteria were patients receiving PDL treatment for traumatic or postoperative scars. Out of these patients, we selected those who were willing to receive telephone interviews or re‐visit at a scheduled time. Eventually, 52 participants were included in our study. A standardized questionnaire was administered to all participants during telephone interviews, encompassing inquiries regarding their medical history, treatment experiences, and the patient component of the Patient and Observer Scar Assessment Scale. Among the enrolled patients, 38 were contacted and interviewed via telephone, while the remaining 14 patients attended follow‐up visits where photographs of their current skin condition were captured. The pretreatment and latest follow‐up photographs obtained from the clinical database were independently scored in a blinded manner by two dermatologist reviewers using both the Vancouver Scar Scale and the Manchester Scar Scale.ResultsAmong the 52 patients, 43 (82.7%) were successfully treated with good response. The correlation coefficients between week‐to‐treatment initiation and posttreatment MSS and VSS among patients with good response were 0.50 (p < 0.001) and 0.46 (p = 0.002), respectively. Given these findings, we established a treatment initiation threshold of 10 weeks, distinguishing patients into early and late treatment groups. The early treatment group showed borderline significantly lower posttreatment MSS and VSS scores than the late treatment group (MSS: 7.5 ± 2.1 vs. 9.3 ± 2.5, p = 0.011; VSS: 2.8 ± 2.0 vs. 4.5 ± 2.3, p = 0.011). Furthermore, both MSS and VSS of posttreatment showed significantly greater improvement in the early treatment group (4.4 ± 1.6 vs. 3.2 ± 1.9; p = 0.03 and 3.8 ± 1.8 vs. 2.8 ± 1.4; p = 0.04).ConclusionsEarly intervention using a PDL within 10 weeks post‐injury achieved better outcomes in treating traumatic and postoperative scars based on both clinical and patient opinions.

Melatonin facilitates oocyte growth in goats and mice through increased nutrient reserves and enhanced mitochondrial function.

Oogenesis involves two phases: initial volumetric growth driven by nutrient accumulation and subsequent nuclear maturation. While melatonin (MLT) has been employed as a supplement to enhance the quality of fully grown oocytes during nuclear maturation phase, its impact on oocyte growth remains poorly studied. Here, we provide invivo evidence demonstrating that follicle-stimulating hormone increases MLT content in ovary. Administration of MLT improves oocyte growth and quality in mice and goats by enhancing nutrient reserves and mitochondrial function. Conversely, MLT-deficient mice have smaller oocytes and dysfunctional mitochondria. Exploring the clinical implications of MLT in promoting oocyte growth, we observe that a brief 2-day MLT treatment enhances oocyte quality and reproductive performance in older mice. These findings highlight the role of MLT in regulating oocyte growth and provide a specific treatment window for optimizing oocyte quality and reproductive performance in female animals.

Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

A Closed-Loop Nanosystem Based on Piezoelectric Sensor and Pd-Nanoshell Photothermal Ablation for Renal Denervation to Treat Hypertension.

Renal sympathetic nerves play a crucial role in the pathogenesis of hypertension, and renal denervation (RDN) is a new solution for patients with refractory hypertension. However, current RDN techniques show inconsistent results in clinical application probably owing to incomplete endovascular ablation of the sympathetic nerves and a lack of measures to localize and assess efficacy. In this study, a closed-loop RDN system consisting of a sensing unit with a piezoelectric thin-film sensor (PTFS) and a treatment unit with a hollow Pd nanoparticle shell (PdNPS) with a diameter of 202.0nm for photothermal neural ablation is constructed. The PTFS can monitor and collect arterial pulsation and blood pressure (BP) and direct PdNPS to maximize RDN. PdNPS maintains a local temperature of 58-62°C under near-infrared-II irradiation (1,064nm) to achieve effective RDN within a range of 90-120s treatment window. Photothermal ablation significantly inhibits the activities of renal sympathetic nerves post-procedure and after one month and reduces the elevation of BP by > 50%. The novel closed-loop system enables safe and efficient targeting, dynamic monitoring, and ablation of the renal sympathetic nerves. This closed-loop system provides a new strategy for RDN technology and even for treating sympathetic nerve-related chronic diseases.

Expression Changes of miRNAs in Humans and Animal Models of Amyotrophic Lateral Sclerosis and Their Potential Application for Clinical Diagnosis.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease. Current detection methods can only confirm the diagnosis at the onset of the disease, missing the critical window for early treatment. Recent studies using animal models have found that detecting changes in miRNA sites can predict the onset and severity of the disease in its early stages, facilitating early diagnosis and treatment. miRNAs show expression changes in motor neurons that connect the brain, spinal cord, and brain stem, as well as in the skeletal muscle in mouse models of ALS. Clinically, expression changes in some miRNAs in patients align with those in mouse models, such as the upregulation of miR-29b in the brain and the upregulation of miR-206 in the skeletal muscle. This study provides an overview of some miRNA study findings in humans as well as in animal models, including SOD1, FUS, TDP-43, and C9orf72 transgenic mice and wobbler mice, highlighting the potential of miRNAs as diagnostic markers for ALS. miR-21 and miR-206 are aberrantly expressed in both mouse model and patient samples, positioning them as key potential diagnostic markers in ALS. Additionally, miR-29a, miR-29b, miR-181a, and miR-142-3p have shown aberrant expression in both types of samples and show promise as clinical targets for ALS. Finally, miR-1197 and miR-486b-5p have been recently identified as aberrantly expressed miRNAs in mouse models for ALS, although further studies are needed to determine their viability as diagnostic targets.

Impact of time intervals on drug efficacy and phenotypic outcomes in acute respiratory distress syndrome in mice

Acute respiratory distress syndrome is a severe lung condition resulting from various causes, with life-threatening consequences that necessitate intensive care. The phenomenon can be modeled in preclinical models, notably through the use of lipopolysaccharide (LPS) instillation in mice. The phenotype induced closely recapitulates the human syndrome, including pulmonary edema, leukocyte infiltration, acute inflammation, impaired pulmonary function, and histological damage. However, the experimental designs using LPS instillations are extremely diverse in the literature. This highly complicates the interpretation of the induced phenotype chronology for future study design and hinders the proper identification of the optimal time frame to assess different readouts. Therefore, the definition of the treatment window in relation to the beginning of the disease onset also presents a significant challenge to address questions or test compound efficacy. In this context, the temporality of the different readouts usually measured in the model was evaluated in both normal and neutrophil-depleted male C57bl/6 mice using LPS-induction to assess the best window for proper readout evaluation with an optimal dynamic response range. Ventilation parameters were evaluated by whole-body plethysmography and neutrophil recruitment were evaluated in bronchoalveolar lavage fluids and in lung tissues directly. Imaging evaluation of myeloperoxidase along with activity in lung lysates and fluids were compared, along with inflammatory cytokines and lung extravasation by enzyme-linked immunoassays. Moreover, dexamethasone, the gold standard positive control in this model, was also administered at different times before and after phenotype induction to assess how kinetics affected each parameter. Overall, our data demonstrate that each readout evaluated in this study has a singular kinetic and highlights the key importance of the timing between ARDS phenotype and treatment administration and/or analysis. These findings also strongly suggest that analyzes, both in-life and post-mortem should be conducted at multiple time points to properly capture the dynamic phenotype of the LPS-ARDS model and response to treatment.

Clinical characteristics and management of functional neurological disorders (FND) mimicking stroke in emergency settings: a functional stroke mimic cases.

FNDs mimicking a stroke represent a growing challenge in the emergency department (ED). A comprehensive diagnostic approach involving clinical evaluation and neuroimaging is essential to differentiate stroke from mimics. The safety profile of thrombolysis justifies its use where FNDs cannot be ruled out. This approach highlights the need for more precise diagnostic tools and protocols to improve patient care and reduce unnecessary treatments. Distinguishing FNDs from actual cerebrovascular events is critical yet difficult, particularly under time constraints. Given the urgency and potential severity of strokes, intravenous thrombolysis is frequently administered even when FNDs cannot be definitively excluded. This retrospective study analyzed data of participants admitted to the Trieste University Hospital Stroke Unit between January 2018 and December 2022, focusing on those presenting with sudden-onset focal neurological deficits mimicking a stroke, with some presenting within the reperfusion treatment window (<4.5 h from symptoms onset). We obtained detailed clinical evaluations and neuroimaging, and administered thrombolytic therapy in selected cases. We included 84 participants presenting with stroke mimics (average age of 45 yo) predominantly female (65.5%). Most common presentations: hemiparesis or hemisensory loss (75%), speech disorder (10.7%), vertigo/gait disorders (4.8%). History of psychiatric disorders was found in 32.1% of cases, and 48.8% had prior neurological disease or stroke risk factors. Advanced neuroimaging was performed in 43 cases yielding normal or non-specific results. Thrombolysis was safely administered in 31%. Patients mostly recovered within the first 24 h from admission (44.7%). We compared this FND's sample with 291 patients with mild ischemic stroke (NIHSS ≤7).

647. INDOCYANINE GREEN (ICG) IDENTIFICATION OF A CISTERNA CHYLI LEAK FOLLOWING RADICAL OESOPHAGO-GASTRECTOMY WITH 2-FIELD LYMPHADENECTOMY: DESCRIPTION OF A NEW TECHNIQUE

Abstract Background Chyle leak is a rare but feared complication post oesophago-gastrectomy, with far-reaching clinical and resource impacts including infection, re-admission and prolonged hospital stay, invasive procedures, and potentially missing the adjuvant therapy window. Low volume leaks can be managed medically via low-fat diet, nutritional support, and somatostatin analogues. Those of higher volume, or where medical management has failed, require radiological or surgical techniques. Where described, these techniques address leaks from a thoracic duct source and are therefore not applicable in patients having undergone oesophago-gastrectomy with radical two- or three- field lymphadenectomy, or where the suspected leak source is from abdominal lymphatics. Methods We report the case of a 78-year-old male diagnosed with cT4a N1 M0 oesophageal adenocarcinoma of the gastro-oesophageal junction. Following neoadjuvant chemotherapy, he underwent robotic-assisted two-phase oesophago-gastrectomy with two-field lymphadenectomy, in which the thoracic duct was identified and ligated. He returned one week post discharge with a left chylothorax. Drinage and medical management were unsuccessful, as were two radiological and one laparoscopic attempt at embolization of the leak. We describe a novel technique utilising indocyanine green (ICG) to identify and facilitate control of a cisterna chyli leak post-oesophago-gastrectomy with radical lymphadenectomy. Results Laparoscopy was performed and indocyanine green injected into the proximal jejunum submucosa, draining via mesenteric lymphatics to the cisterna chyli. Subsequent thoracoscopy revealed a prominent lymphatic channel around the left crus which was ligated. However, further leak was seen through the hiatus upon administration of high-fat jejunostomy feed. Re-laparoscopy revealed a leak from the cisterna chyli which was successfully ligated with ethibond sutures, leading to cessation of chyle leak and successful discharge of the patient, who subsequently received adjuvant therapy within the treatment window. Conclusion We describe a safe and effective novel technique for management of chyle leak from abdominal lymphatics or the cisterna chyli following oesophago-gastrectomy with radical two-field lymphadenectomy. https://drive.google.com/file/d/1nCNnowdJVPlV0GOleXVNVMshuU19kCb/view?usp=sharing

The mitochondrial division inhibitor Mdivi-1 protected organ function and extended the treatment window in rats with uncontrolled haemorrhagic shock.

To elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. Before definitive haemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg and 1 mg/kg) was administered to uncontrolled haemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss, fluid demand, survival time, vital organ function, myocardial mitochondrial structure, and mitochondrial function of the heart, liver, kidney and intestine, and oxidative stress at 1 hour after hypotensive resuscitation (50-60 mmHg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive haemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 hours. Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 hours in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping

The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devise a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies.

New Data Suggest Longer Treatment Window for Dementia in Parkinson's Disease

New Data Suggest Longer Treatment Window for Dementia in Parkinson's Disease