Rate Response Research Articles

SOX/FOLFOX+nivolumab followed by conversion surgery for HER2 negative primary gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors: Early results of a consecutive 41 cases.

487 Background: Gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors could be cured by conversion surgery after primary chemotherapy. Because SOX/FOLFOX plus Nivolumab showed high clinical response regardless of CPS score, this nivolumab-based chemotherapy followed by surgery may be promising strategy for these tumors. Methods: The study examined the patients who had HER2 negative primary gastric or gastroesophageal junction cancer with synchronous oligo-metastasis or borderline resectable tumors. Oligo-metastasis was defined as peritoneal dissemination localized to the upper abdomen, para-aortic lymph node metastasis, liver metastasis limited up to 3 segments, mediastinal lymph node metastasis, ovarian metastasis, or esophageal intramural metastasis. Borderline resectable tumors were defined as regional lymph node metastasis forming bulky mass or primary tumors invading adjacent organs. The patients with these tumors were treated with primary chemotherapy with SOX/FOLFOX plus Nivolumab for 3 to 22 months, then were proceeded to conversion surgery in case the tumors are responded to chemotherapy and are considered to achieve R0 resection based on the MDT conference. Results: During November 2021 and February 2024, 41 consecutive patients were included in the study. Disease status was peritoneal dissemination in 1, para-aortic lymph node metastasis in 26, liver metastasis in 5, mediastinal lymph node metastasis in 1, ovarian metastasis in 1, esophageal intramural metastasis in 2, bulky nodal metastasis in 6, and primary tumors invading pancreas in 1 (distant oligo-metastasis in 34 patients and borderline resectable in 7). CPS score was >5 in 13, 5> and >1 in 23, and >1 in 5 patients. Chemotherapy regimen was SOX+Nivo in 38 and FOLFOX+Nivo in 3. Of 41 patients, 33 (80.5%) (SOX+Nivo: 30, FOLFOX+Nivo: 3) were proceeded to the conversion surgery, and 32 patients achieved R0 resection. 6 patients showed disease progression and 2 patients were judged as unresectable. Major pathological response (disappearance more than 80% of the primary tumor) rate was 54.5% (18/33) and pCR rate was 33.3% (11/33). Conclusions: SOX/FOLFOX plus Nivolumab for HER2 negative gastric or gastroesophageal junction cancer with oligo-metastasis or borderline resectable tumors achieved a high R0-conversion surgery rate and pathological response rate.

Tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) + FOLFIRI in 2L+ colorectal adenocarcinoma (CRC): Preliminary results from a phase 1 study.

129 Background: DR5, a proapoptotic receptor, is selectively expressed on tumor vs normal cells, making it an attractive target. DR5 binds to its ligand, TRAIL, resulting in DR5 multimerization and apoptosis; greater DR5 clustering enhances downstream effects. Ozekibart is a next-generation, recombinant, humanized, tetravalent DR5 agonist that is based on a single-domain antibody platform and precisely engineered to balance agonism and safety. Ozekibart previously demonstrated an acceptable safety profile and clinical benefit in chondrosarcoma (1), prompting a phase 2, randomized trial (ChonDRAgon; NCT04950075). An ongoing phase 1 study (NCT03715933) is evaluating ozekibart in various solid tumors, including 2L+ CRC, for which effective therapies are lacking. We present preliminary results of ozekibart + FOLFIRI in 2L+ CRC (data cutoff: Aug 9, 2024). Methods: Parts 1 (single-agent dose escalation) and 2 (single-agent dose expansion; recommended phase 2 dose [RP2D] ozekibart 3 mg/kg IV Q3W) of this 3-part, open-label trial are complete. Part 3 (combination dose expansion with chemo) is ongoing in pts with CRC, Ewing sarcoma, or SDH-deficient GIST. Pts with locally advanced or metastatic, unresectable CRC who received oxaliplatin-based chemo were eligible for part 3. Pts with chronic liver disease were ineligible. Pts in the part 3 CRC cohorts (N=13; enrollment complete) received ozekibart 1 mg/kg (n=5) or 3 mg/kg (n=8) IV Q28D (1 cycle) + FOLFIRI Q14D (FOLFIRI could be stopped after ≥6 cycles); in 4/5 pts, ozekibart dose was escalated to 3 mg/kg (RP2D). The primary endpoint is safety; clinical response is an exploratory endpoint. Results: In total, 13 pts with CRC (male, 62%) received ozekibart + FOLFIRI. Median age was 60. All pts had metastatic disease; median number of prior lines of therapy was 2 (range, 1-6). At data cutoff, 2 pts remained on treatment. Ozekibart-related adverse events (AEs) were reported in 85% of pts (grade ≥3, 31%) and led to ozekibart interruption in 3 pts and discontinuation in 1 pt. One combo-related AE (neutropenic sepsis) led to death. The most common ozekibart-related AEs were nausea (n=5) and diarrhea, fatigue, and increased alanine aminotransferase (each n=4). Four pts (31%) had responses (all partial). Disease control rate (response + stable disease) was 77% (10/13) and durable (>180 days) in 46% (6/13) of pts. Most pts had tumor shrinkage. Median PFS was 7.85 mo. Conclusions: Ozekibart + FOLFIRI showed encouraging preliminary efficacy, including PRs and durable disease control, as 2L+ therapy in pts with CRC. Given these promising data, a new expansion cohort (C4d) is open to validate these findings in a more homogeneous population. Eligible pts will have had 2 or 3 prior lines of systemic therapy (irinotecan allowed but not in the immediately prior line) and must have archival or fresh biopsy tissue. 1. Subbiah. Clin Cancer Res. 2023. Clinical trial information: NCT03715933 .

Perioperative chemoimmunotherapy for patients with gastric or gastroesophageal junction cancer: A systematic review and meta-analysis.

430 Background: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, in combination with chemotherapy, are known to improve survival in advanced/metastatic gastric (GC) or gastroesophageal junction cancer (GEJC). Therefore, several trials incorporated ICIs in the neoadjuvant/peri-operative setting with promising preliminary results. The purpose of this meta-analysis was to determine the safety and efficacy of neoadjuvant chemoimmunotherapy for resectable GC or GEJC. Methods: PubMed/MEDLINE and Embase were systematically searched for randomized control trials (RCTs) investigating the efficacy of neoadjuvant anti PD-1/PD-L1 ICIs for locally advanced GC or GEJC up to 07/27/2024. Outcomes of interest were surgical outcomes such as pathological complete response (pCR) rate and major pathological response (MPR) rate. Risk ratio (RR) with 95% confidence intervals (CI) were pooled using a fixed model meta-analysis. Statistical analysis was performed with Review Manager 5.4.1. I² statistics was used to assess heterogeneity. The Cochrane risk of bias assessment tool was used to assess the risk of bias. All analyses were conducted at a significance level of 0.05. Results: Seven RCTs comprising 2,911 GC or GEJC patients were included. Among these, 1,454 patients received neoadjuvant chemoimmunotherapy and 1,457 patients received chemotherapy, respectively. Neoadjuvant chemoimmunotherapy significantly improved pCR rate (RR 2.94; 95% CI 2.34-3.70; P<0.00001; I 2 =33%), and MPR rate (RR 1.47; 95% CI 1.25-1.72; P<0.00001; I 2 =30%) compared to chemotherapy alone. Chemoimmunotherapy was associated with slightly higher incidence of grade 3 or worse treatment-related adverse events than chemotherapy (RR 1.07; 95% CI 1.01-1.14; p=0.03; I 2 =0%). Conclusions: This meta-analysis showed that adding ICIs to chemotherapy significantly improved the pCR and MPR rates and was feasible for patients with locally advanced GC or GEJC. Results of survival outcomes in the included trials and ongoing trials are awaited to further determine the efficacy and utility of chemoimmunotherapy and identify patient populations that benefit from this strategy. Included studies. Author Year Trial# Design Cancer; Stage Name of IO Target Chemo regimen Extracted data pCR MPR TRAE Ding X 2023 NCT04982939 P2 G/GEJ; Stage2-3 Sintilimab PD-1 SOX ○ ○ Janjigian YY 2023 NCT04592913 P3 G/GEJ; ≥T2Nany/T0-4 N+ Durvalumab PD-L1 FLOT ○ ○ Li C 2023 NCT04208347 P3 G/GEJ; T3-4aN+ Camrelizumab PD-1 SOX(+apatinib) ○ ○ Lin JX 2024 NCT04195828 P2 G; T2-4N+ Camrelizumab PD-1 S-1+nabPTX ○ ○ ○ Lorenzen S 2024 NCT03421288 P2 G/GEJ; ≥T2 and/or N1 Atezolizumab PD-L1 FLOT ○ ○ Peng Z 2024 NCT04661150 P2 G/GEJ HER2+; resectable Atezolizumab PD-L1 CAPOX+Tmab ○ Shitara K 2024 NCT03221426 P3 G/GEJ; ≥T3N+ Pembrolizumab PD-1 FLOT or XP/FP ○ ○ Yuan SQ 2024 NCT04250948 P2 G/GEJ; T3-4N+ Toripalimab PD-1 SOX/CAPOX ○ ○ ○

Real-world experience with atezolizumab plus bevacizumab (A+/-B) in Hispanic patients with advanced hepatocellular carcinoma (HCC) at a Hispanic-majority cancer center.

549 Background: Combination of atezolizumab (A), a programmed death-ligand 1 (PD-L1) inhibitor, and bevacizumab (B), a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated efficacy for first-line treatment for HCC. However, real-world data on the outcomes of this combination therapy in diverse patient populations, particularly in Hispanic U.S. patients, remains limited. This study aims to evaluate the clinical outcomes of patients intended to treat with A+/-B at a Hispanic-majority U.S. cancer center. Methods: This retrospective study of patients diagnosed with advanced unresectable HCC who received treatment with A+B at a Hispanic-serving NCI-designated cancer center. Patients were included if they received at least one dose of A, either as monotherapy or in combination with B, between January 2019 and April 2022. Demographic and clinical data, including age, gender, ethnicity, liver disease etiology, Child-Pugh (CP) classification, comorbidities, and treatment details, were collected. The primary endpoints were the overall response rate (ORR) and complete response (CR) rate. Statistical analyses were conducted to evaluate the association between baseline characteristics and clinical outcomes. The median overall survival (mOS) evaluated by Kaplan-Meier Method. Results: 38 patients received at least A (84% A+B, 6 patients had B held due to bleeding risk after consent). Median age 65 years (45-90). 32 (84%) patients were male. 22 (58%) patients were Hispanic. 45% had HCV-related liver disease. 32% had CP B with no statistically significant association between CP Class and ethnicity. 53% had concurrent diabetes. 26% patients had obesity. The median time on treatment was 7.5 mo (1- 24 mo) with no statistical difference between Hispanics and non-Hispanics (9 vs 6 mo, p 0.70). CR 37% with ORR of 42%. Using Fisher’s exact test, no association was noted between obesity, ethnicity, treatment option or CP class to occurrence of complete or partial response. mOS was 19 mo. There was no statistical difference in mOS between CP A and CP B (19 vs 10 mo, p value 0.6) and no difference between Hispanics (14 mo) vs non-Hispanics (19 mo) (p 0.5), using log rank test. Conclusions: This real-world analysis of a Hispanic-majority U.S. cohort of patients with advanced HCC shows 42% ORR and 37% CR. The findings suggest that this regimen is effective across a diverse patient population, including those with comorbid conditions, such as liver dysfunction (CP B 32%), HCV (45%), diabetes (53%, and obesity (26%). Limitations are the small study population and retrospective nature of the study. Evaluation of toxicity data is ongoing. Further prospective studies are needed to identify biomarkers of outcomes in Hispanic patients with HCC, which is ongoing at our cancer center (NCT03894917).

Impact of free water on strain rate response of concrete in compression with a fully coupled DEM/CFD approach

Impact of free water on strain rate response of concrete in compression with a fully coupled DEM/CFD approach

P1178 A multi-centred retrospective cohort study comparing JAK inhibitor therapies in moderate to severe ulcerative colitis

Abstract Background Tofacitinib, filgotinib and upadacitinib are JAK inhibitors (JAKi) that are licensed for treatment in moderate to severe ulcerative colitis (UC). Whilst these drugs have demonstrated efficacy against placebo, there is no head-to-head data. This study aims to compare the clinical efficacy between these drugs. Methods This is a multi-centred, retrospective cohort study with data collected from January 2018 to June 2024. Patients with UC were recruited on their first JAKi, irrespective of previous advanced therapies. Clinical remission (faecal calprotectin (FCP) <250, Mayo £1, UCEIS £1, pMayo £2, SCCAI £2) and response (50% reduction in FCP from baseline, reduction in partial Mayo or UCEIS by 3 or more, or sustained <3) was measured at 3- and 6-months. If a patient stopped taking JAKi, they were considered to have failed both response and remission. Data was non-parametric and outcome measures were compared using Chi-squared tests. Results There was a total of 266 patients included in the final analysis. 70 (26%) were on upadacitinib, 47 (18%) on filgotinib and 149 (56%) on tofacitinib (Table 1). At least 87% (129/149) on tofacitinib had exposure to a previous biologic compared to 80% (56/70) for upadacitinib and 66% (31/47) for filgotinib. At 3-months, clinical response in upadacitinib, filgotinib and tofacitinib was demonstrated in 83%, 74% and 75% patients, respectively and clinical remission was seen in 69%, 64% and 52%, respectively. At 6-months, clinical response was demonstrated in 79%, 65% and 63%, respectively and remission was seen in 75%, 61% and 51%, respectively. Upadacitinib demonstrated significantly higher 3-months remission rate (p=0.019) and 6-months response (p=0.010) and remission rates (p= 0.001) compared to tofacitinib. In the bio-exposed cohorts, upadacitinib demonstrated greater 6-months remission rates (71%) compared to 64% on filgotinib (p=NS) and 52% tofacitinib (p= 0.022). In bio-naïve cohorts (n=50), upadacitinib demonstrated greater 6-months remission rates (93%) compared to 56% on filgotinib (p=0.024) and 50% tofacitinib (p= 0.009). Combining the JAKi, 90% of patients were not on steroids at 3-months and 94% were not on steroids at 6-months. A total of 26 patients had a colectomy at the time of their JAKi, 17 on tofacitinib, 5 on filgotinib and 4 on upadacitinib. Conclusion This study demonstrates that upadacitinib is more likely to achieve 3- and 6-month remission compared to tofacitinib. In a small sub-group of bio-naïve patients Upadacitinib was more likely to achieve 6-month remission compared to filgotinib and tofacitinib. JAKi were associated with minimal adverse events and importantly, the efficacy of JAKi does not appear diminished by prior biologic use.

Improved brain functional network in major depressive disorder with suicidal ideation after individual target-transcranial magnetic stimulation treatment: a graph-theory analysis

IntroductionMajor depressive disorder with suicidal ideation (MDD/SI+) is characterized by high prevalence, high recurrence rate, high disability rate and low response rate. There is an urgent need for clarifying the pathogenesis and developing novel treatment methods.MethodsSubjects were recruited for the collection of Magnetic Resonance Imaging data and clinical scales. Individual target-transcranial magnetic stimulation (IT-TMS) using Stanford Neuromodulation Therapy over individualized left dorsolateral prefrontal cortex was performed to treat MDD/SI+ with the ethical approval (KY20212218-C-1). GRETNA software was used to analyze brain network characteristics according to graph theory.ResultsA total of 32 patients (aged 18-55) and 28 healthy controls (aged 20-51) had been recruited. Patients after IT-TMS treatment had significant reduction in suicidal ideation and depressive symptom. The functional network of all three groups conformed to small-world topology. There was a renormalization in topology structure after IT-TMS treatment. Decreased functional connectivity between right insula and left anterior cingulate gyrus correlated with improvement in Beck Scale for Suicide Ideation scores.DiscussionThe current study highlights that MDD/SI+ patients in this cohort showed abnormal brain network connections compared to healthy controls, and that IT-TMS may exert its treatment effects by reducing spontaneous hyper-connectivity in the salience network and insula.

The associations between cardiovascular and pain responses to a cold pressor test differ between males and females.

Nociceptors contribute to the cardiovascular responses during a cold pressor test (CPT). While these responses are lower in females, data suggest that they perceive the CPT as more painful. Thus, we examined sex differences in associations between pain and cardiovascular responses to a CPT (Aim 1) as well as differences between females using (OC), and not using (NC), an oral contraceptive (Aim 2). 25 males (23 ± 5years) and 25 females (21 ± 3years; 11OC and 14NC) were studied. Cardiovascular data and pain levels (0-10 scale) were recorded at baseline then during a two-minute CPT; changes from baseline to peak response were analyzed. Systolic blood pressure (SBP, p = 0.57), mean arterial pressure (MAP, p = 0.22), heart rate (HR, p = 0.58), and pain (p = 0.71) responses did not differ between sexes; diastolic blood pressure (DBP) increased more in males (17 ± 8 vs. 13 ± 6mmHg, p < 0.05). Pain was associated with HR in males (r = 0.42, p < 0.05) but notfemales (r = -0.16, p = 0.44); no other associations were observed in either sex (p = 0.48-0.92). SBP (27 ± 12 vs. 15 ± 6mmHg), DBP (16 ± 6 vs. 9 ± 5mmHg), MAP (20 ± 7 vs. 14 ± 5mmHg), and HR (8 ± 5 vs. 2 ± 5beats/min) were greater in NC than OC (p < 0.05 for all); pain was similar (p = 0.38). In NC, pain was associated with DBP (r = 0.65, p = 0.01)and MAP (r = 0.65, p = 0.01),but not HR (r = -0.43, p = 0.13), and tended to be associated with SBP (r = 0.46, p = 0.09). In OC, pain was inversely associated with SBP (r = -0.62, p < 0.05) but no other outcome (p = 0.40-0.65). We report a sexual dimorphism in the HR-pain association during a CPT and underscore the impact of oral contraceptives.

Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

Correlating autonomic physiology with symptoms of autonomic dysreflexia after spinal cord injury.

Individuals with spinal cord injury (SCI) commonly have autonomic dysreflexia (AD) with increased sympathetic activity. After SCI, individuals have decreased baroreflex sensitivity and increased vascular responsiveness. To evaluate the relationship between baroreflex and blood vessel sensitivity with AD symptoms. Case control. Tertiary academic center. 14 individuals with SCI, 17 matched uninjured controls. All participants quantified AD symptoms using the Autonomic Dysfunction Following SCI (ADFSCI)-AD survey. Participants received three intravenous phenylephrine boluses, reproducibly increasing systolic blood pressure (SBP) 15-40 mmHg. Continuous heart rate (R-R interval, ECG), beat-to-beat blood pressures (Finapres), and popliteal artery flow velocity were recorded. Vascular responsiveness (α1 adrenoreceptor sensitivity) and heart rate responsiveness to increased SBP (baroreflex sensitivity) were calculated. Baroreflex sensitivity after increased SBP; Vascular responsiveness through quantified mean arterial pressure (MAP) 2-minute area under the curve and change in vascular resistance. SCI and control cohorts were well matched with mean age 31.9 and 29.6 years (p = .41); 21.4% and 17.6% female, respectively. Baseline MAP (p = .83) and R-R interval (p = .39) were similar. ADFSCI-AD scores were higher following SCI (27.9 ± 22.9 vs. 4.2 ± 2.9 in controls, p = .002). To quantify SBP response, MAP area under the curve was normalized to dose/body weight. Individuals with SCI had significantly larger responses (0.26 ± 0.19 mmHg*s/kg*μg) than controls (0.06 ± 0.06 mmHg*s/kg*μg, p = .002). Similarly, leg vascular resistance increased after SCI (24% vs. 6% to a normalized dose, p = .007). Baroreflex sensitivity was significantly lower after SCI (15.0 ± 8.3 vs. 23.7 ± 9.3 ms/mmHg, p = .01). ADFSCI-AD subscore had no meaningful correlation with vascular responsiveness (R2 = 0.008) or baroreflex sensitivity (R2 = 0.092) after SCI. Although this confirms smaller previous studies suggesting increased α1 adrenoreceptor sensitivity and lower baroreflex sensitivity in individuals with SCI, contrary to our hypothesis these differences lacked correlation to increased symptoms of AD. Further research into physiologic mechanisms is needed to explain why some individuals with SCI develop symptoms.

Unveiling whole body vibration squat intensity insight from oxygen consumption and heart rate response

This study explored the effects of training weight and amplitude in whole-body vibration (WBV) on exercise intensity, indicated by oxygen consumption (VO2) and heart rate. In LOAD-study: ten participants performed squats under non-WBV and WBV (30 Hz 2 mm) conditions at 0%, 40%, and 80% bodyweight (BW). In AMPLITUDE-study: eight participants performed squats under non-WBV, low-amplitude WBV (30 Hz 2 mm), and high-amplitude WBV (30 Hz 4 mm) conditions with 0% and 40%BW. heart rate and VO2 were continuously recorded. Metabolic equivalents (METs) for WBV squats with 0–40% BW were ~ 3.8–5.3, and ~ 7.3 for 80% BW. LOAD-study presented a significant vibration × training weight interaction effect for in-exercise VO2 (F = 3.171, P = 0.05, ηp2 = 0.105) and post-exercise VO2 (F = 4.156, P = 0.021, ηp2 = 0.133). In-exercise VO2 of 80%BW squat (P < 0.001) and post-exercise VO2 of both 40% (P = 0.049) and 80%BW squat (P < 0.001) under WBV were significantly higher than those under non-WBV. AMPLITUDE-study presented no significant amplitude × training weight interaction effect for VO2 and heart rate (P > 0.05). WBV squats are moderate-to-vigorous intensity exercise. 30 Hz 2 mm WBV is sufficient for evoking superior oxygen consumption during and after exercise under certain training weight, the response of heart rate to WBV was less pronounced. Increasing training weight could elicit greater oxygen consumption and heart rate under WBV condition.

Cerebral Hemodynamic Responses to Disease-Modifying and Curative Sickle Cell Disease Therapies.

Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Treatments include oral hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation (HSCT). Our objective was to evaluate the neurologic relevance of these therapies by characterizing how treatment-induced changes in hemoglobin (Hb) affect brain health biomarkers. In this interventional study, adults with and without SCD underwent a 3T-MRI at Vanderbilt University Medical Center at 2 time points before and after clinically indicated transfusion or HSCT or at 2 time points without the introduction of a new Hb-altering therapy (adult controls and patients with SCD on hydroxyurea). Cerebral blood flow (CBF; mL/100 g/min) and cerebral venous blood relaxation rate (s-1; a marker of Hb and blood oxygen content) responses were assessed to understand how these markers of brain health vary with Hb modulation. CBF was assessed with arterial spin labeling MRI, and blood relaxation rate was assessed using T2 relaxation under spin tagging MRI. Measures were pairwise compared within each cohort using a 2-tailed Wilcoxon signed-rank test, and regression was applied to evaluate the parameter and Hb change relationships. The significance criterion was 2-sided p < 0.05. Adults with (n = 43; age 28.7 ± 7.7 years; 42% male) and without (n = 13; age 33.5 ± 12.2 years; 46% male) SCD were evaluated. In adults receiving hydroxyurea (n = 10), neither Hb, CBF, nor venous relaxation rate changed between time 1 (Hb = 8.6 ± 1.2 g/dL) and time 2 (Hb = 9.0 ± 1.8 g/dL) (all p > 0.05). In transfusion patients (n = 19), Hb increased from 8.2 ± 1.4 g/dL to 9.3 ± 1.3 g/dL before vs after transfusion (p < 0.001), paralleling a CBF decrease of 14.2 mL/100 g/min (p < 0.001) toward control levels. The venous relaxation rate did not change after transfusion (p = 0.71). In HSCT patients (n = 14), Hb increased from 8.9 ± 1.9 g/dL to 12.9 ± 2.7 g/dL (p < 0.001) before vs after transplant, paralleling CBF decreases from 68.16 ± 20.24 to 47.43 ± 12.59 mL/100 g/min (p < 0.001) and increase in venous relaxation rate (p = 0.004). Across the Hb spectrum, a CBF decrease of 5.02 mL/100 g/min per g/dL increase in Hb was observed. Findings demonstrate improvement in cerebral hemodynamics after transfusion and transplant therapies compared with hydroxyurea therapy; quantitative relationships should provide a framework for using these measures as trial end points to assess how new SCD therapies affect brain health.

Effects of 6 months of endurance exercise on motor function, exercise capacity, and autonomic function based on presence of autonomic dysfunction in individuals with early Parkinson's disease

Background Endurance exercise improves aerobic capacity (VO2peak) and motor symptoms in people with early Parkinson's disease (PD). Some people with PD exhibit signs of chronotropic incompetence (CI), which may impact exercise-induced benefits. Objective We investigated whether CI in people with early PD influences the change in motor signs, VO2peak, and peak heart rate (HR) following 6 months of endurance exercise. Methods We performed secondary analyses of the Study in Parkinson's Disease of Exercise (SPARX), which randomized people with early PD into a high-intensity endurance exercise [80–85% of peak HR], moderate-intensity endurance exercise [60–65% of peak HR], or usual care group. MDS-UDPRS Part 3 score, VO2peak, and heart rate (HR) response to maximal cardiopulmonary exercise testing (CPET) were analyzed at baseline and following 6 months of exercise. Participants were divided into three groups: 1) normal chronotropic response at baseline, 2) CI at baseline, and 3) taking medications with a known negative chronotropic effect regardless of CI status. Results Data from 119 individuals (64.0 ± 9.0 years, 57.1% male, 0.3 years since diagnosis [median]) were analyzed. There were no differences among the groups in change in MDS-UPDRS motor score ( p = 0.953), VO2peak ( p = 0.965), or peak HR ( p = 0.388). People randomized into the high-intensity group improved VO2peak compared to usual care ( p &lt; 0.001adj) regardless of CI status. Conclusions Baseline CI did not alter responses to endurance exercise in those with early PD, suggesting that the beneficial effects of endurance exercise on disease progression and VO2peak in people with early PD apply equally to people with CI.

A Method for Imaging the Ischemic Penumbra with MRI using IVIM.

In acute ischemic stroke, the amount of "local" CBF distal to the occlusion, i.e. all blood flow within a region whether supplied antegrade or delayed and dispersed through the collateral network, may contain valuable information regarding infarct growth rate and treatment response. DSC CBF using a local arterial input function (AIF) is one method of quantifying local CBF (local-qCBF) and correlates with collaterals. Similarly, intravoxel incoherent motion MRI (IVIM) is "local", with excitation and readout in the same plane, and a potential alternative way to measure local-qCBF. The purpose of this work was to compare IVIM local-qCBF against DSC local-qCBF in the ischemic penumbra, compare measurement of perfusion-diffusion mismatch (PWI/DWI), and examine if local-qCBF may improve prediction of final infarct. Eight experiments in a pre-clinical canine model of middle cerebral artery occlusion were performed; native collateral circulation was quantified via x-ray DSA 30 minutes post-occlusion, and collateralization was subsequently enhanced in a subset of experiments with simultaneous pressor and vasodilator. IVIM and DSC MRI were acquired 2.5hr post-occlusion. IVIM was post-processed to return local-qCBF from fD*, water transport time (WTT) from D*, diffusion from D, and the PWI/DWI mismatch. These were compared with DSC parameters processed first with a standard global-AIF and then with a local-AIF. These DSC parameters included time-to-maximum, local MTT, standard-qCBF, local-qCBF and PWI/DWI mismatch. Infarct volume was measured with DWI at 2.5hrs and 4hrs post-occlusion. 2.5hr post-occlusion, IVIM local-qCBF in the non-infarcted ipsilateral territory strongly correlated with DSC local-qCBF (slope=1.00, R2=0.69, Lin's CCC=0.71). Correlation was weaker between IVIM local-qCBF and DSC standard-qCBF (R2=0.13). DSC localqCBF and IVIM local-qCBF in the non-infarcted ipsilateral territory both returned strong prediction of final infarct volume (R2=0.78, R2=0.61 respectively). DSC standard-qCBF was a weaker predictor (R2=0.12). The hypoperfused lesion from DSC local-qCBF and from IVIM local-qCBF both predicted final infarct volume with good sensitivity and correlation (slope=2.08, R2=0.67, slope=2.50, R2=0.68 respectively). The IVIM PWI/DWI ratio was correlated with infarct growth (R2=0.70) and WTT correlated with DSC MTT (R2=0.60). Non-contrast IVIM measurement of local-qCBF and PWI/DWI mismatch may include collateral circulation and improve prediction of infarct growth. AIF: arterial input function, IVIM: intravoxel incoherent motion, qCBF: quantitative cerebral blood flow, WTT: water transport time, MCAO: middle cerebral artery occlusion, MD: mean diffusivity.

A novel method for the measurement of cardiovascular responses to lower body negative pressure in the awake instrumented rat.

Lower body negative pressure (LBNP) has been used for decades in humans to model arterial baroreceptor unloading and represents a powerful tool for evaluating cardiovascular responses to orthostatic challenges. However, LBNP studies in animals have been limited to conditions of anesthesia or sedation, where cardiovascular reflexes are altered. Given the consequent uncertainties, the usefulness of LBNP studies in these preclinical models has been severely hampered. Here, we developed an approach using a novel system to study LBNP responses in awake rats instrumented for telemetric blood pressure (BP) measurement. BP responses to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by measurements under various treatments. In awake untreated rats, BP was well maintained up to -15 mmHg LBNP and there was a robust baroreceptor response in heart rate (HR). Under anesthesia with 3% isoflurane, BP was not maintained at LBNP below -3 mmHg and baroreceptor responses in HR were completely blocked, confirming the limited usefulness of this method under anesthesia. Interrogation of the autonomic pathways involved in the response revealed that muscarinic (atropine) and β1-adrenergic (atenolol) blockade, separately or together, blocked the HR responses, but BP remained well maintained. α1-adrenergic blockade (prazosin) severely blunted the ability to maintain BP in response to LBNP. These data are consistent with findings in human subjects in that the vascular component of the orthostatic reflex predominates in preserving BP. Validation of this novel method provides a valuable tool for investigating orthostatic (in)tolerance in a facile preclinical model.NEW & NOTEWORTHY Orthostatic hypotension or intolerance is a common but often underappreciated disorder that is associated with a variety of neurological comorbidities. LBNP studies provide a valuable tool to study these conditions, but heretofore could only be used in human subjects, since animal subjects needed to be anesthetized or sedated, which blunts or eliminates neurocardiovascular reflexes. This novel method allowing LBNP studies in awake rats will provide a valuable preclinical model for studying these disorders.

Efficiency and safety of HAIC combined with lenvatinib and tislelizumab for advanced hepatocellular carcinoma with high tumor burden: a multicenter propensity score matching analysis.

The present work focused on assessing whether hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and tislelizumab was safe and effective on advanced hepatocellular carcinoma (HCC) showing high tumor burden. In the present multicenter retrospective study, treatment-naive advanced HCC patients (BCLC stage C) showing high tumor burden (maximum diameter of intrahepatic lesion beyond 7cm) treated with lenvatinib and tislelizumab with or without HAIC were reviewed for eligibility from June 2020 to June 2023. Baseline differences between groups were mitigated by propensity score matching (PSM). Our primary endpoint was overall survival (OS); and secondary endpoints included adverse events (AEs), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR) according to RECIST 1.1 criteria, respectively. After eligibility reviewed, total 162 patients treated with lenvatinib and tislelizumab were enrolled: 63 patients with HAIC (HTP group), and the remaining 99 patients without HAIC (TP group). After PSM 1:1, 47 cases were evenly divided into each group. Of them, HTP group showed significant prolonged median OS compared with TP group (16.6 versus 21.0 months; hazard ratio [HR]: 0.26, 95% confidence interval [CI]: 0.35-0.98; p = 0.039), and median PFS of HTP group was also prolonged (8.9 versus 11.6months; HR: 0.55, 95% CI: 0.34-0.87; p = 0.010). Higher DCR and ORR could be observed in HTP relative to TP groups (ORR: 53.2% versus 17.0%, p < 0.001; DCR: 87.2% versus 61.7%, p = 0.004). The severe AEs (grade 3/4) and all grades were comparable between the groups, while all of these AEs could be controlled, and AEs of grade 5 were not reported. HAIC combined with lenvatinib and tislelizumab is the candidate treatment for advanced HCC patients because of its improved prognosis and acceptable safety.

Real-world experiences with brentuximab vedotion-based regimens in systemic anaplastic large cell lymphoma: a multi-center retrospective study.

Brentuximab vedotin (BV) has demonstrated high remission rates in clinical trials for systemic anaplastic large cell lymphoma (sALCL), yet its real-world effectiveness in China remains unconfirmed. This retrospective observational study evaluates BV-based regimens in patients with sALCL, treated from 2020 to 2023. A multi-center observational retrospective study was conducted on patients with sALCL received BV plus cyclophosphamide, doxorubicin, and prednisone (CHP) upfront or BV plus gemcitabine, oxaliplatin(GemOx), gemcitabine, cisplatin, dexamethasone(GDP), or isocyclophosphamide, carboplatin, etoposide (ICE)for later lines. Primary endpoints were complete response rate (CRR) and overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and the incidence of adverse events (AEs). Among the 38 patients (28 newly diagnosed and 10 with refractory/relapsed disease), the ORR were 100% (with 89.3% CR) for newly diagnosed patients and 70% (with 50% CR) for refractory/relapsed patients. The median duration of response was 14 months for newly diagnosed patients and 23.8 months for those with refractory/relapsed disease. 2-year Survival rates were 100% for newly diagnosed patients and 80% for refractory/relapsed patients, with 2-year PFS rates of 92.8% and 70%, respectively. Neurological toxicities were commonly observed but resolved following the completion of treatment. BV has proven to be effective and well-tolerated in real-world settings for the treatment of sALCL, reinforcing its potential as a promising option for first-line or subsequent therapy. The sustained efficacy observed post-CR suggests that these patients may have a prolonged disease control.

Verbal Memory is Higher After Aerobic Exercise When Compared to Muscle Stretching.

Acute exercise is linked to memory improvement. Several mediators may influence the effect of exercise such as the type of exercise (aerobic exercise, muscle stretching). Purpose: The primary aim was to analyze memory outcomes after a 20-min bout of aerobic exercise or muscle stretching. Methods: 42 healthy participants ages 18-35 were randomized to perform 20min of either moderate-intensity aerobic exercise (AE) on a treadmill or muscle stretching exercise (SE). After exercise, memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT). The relationship between exercise heart rate and memory outcomes were evaluated within each group. Results: Immediate learning as well as delayed recall was higher after AE compared to SE. Heart rate during exercise correlated with immediate learning in the AE group only. Conclusion: Acute exercise that elicits a heart rate response may be important for improving memory.

Response of Crop Yield and Productivity Contribution Rate to Long-Term Different Fertilization in Northeast of China.

To reveal the changes in crop yield and contribution rate of black soil productivity under long-term different fertilization conditions in black soil areas and to find the important significance of fertilization for sustainable and stable crop yield, high yield, and improving the contribution rate of black soil nutrients. Based on the long-term experiment of black soil fertility in Harbin, the Ministry of Agriculture and Rural Affairs, under the maize-wheat-soybean rotation system, crop yield, sustainability and stability of yield, the contribution rate of black soil productivity, and natural nutrient supply capacity under 10 fertilization treatments (CK, NP, NK, PK, NPK, M, MNP, MNK, MPK, and MNPK) were analyzed. Results showed that, compared with the treatment of chemical fertilizer, yields of maize, wheat, and soybeans increased under treatment of organic fertilizer combined with chemical fertilizer, among which the yields of maize and wheat changed the most. As the rotation period lengthened, the sustainable yield index (SYI) values of chemical fertilizer treatment and its combination with organic fertilizer treatment gradually decreased. During the rotation period, the SYI value follows: chemical fertilizer combined with organic fertilizer > chemical fertilizer > organic fertilizer. The coefficient of variation (CV) of yield stability showed an overall trend of increasing first and then decreasing, with individual treatments showing a gradual increasing trend (NP and NPK; MNP and MNPK). Under different rotation periods, the overall contribution rate of soil productivity of long-term organic fertilizer combined with chemical fertilizer treatment was higher than that of single chemical fertilizer treatment. With the extension of the rotation period, the contribution rate of soil productivity of NPK treatment was higher and slightly increased, while other treatments showed a downward trend. Although the contribution rate of soil productivity of organic-inorganic fertilizer combined treatment (MNP and MNK) showed a downward trend, it still remained at a high level (97.2% and 95.9%). In addition, the black soil has strong phosphorus and potassium supply capacity; nitrogen was lower than those two elements, with an average natural potassium supply capacity of 94.0-97.1%. Therefore, the combination of organic and inorganic fertilizers is one of the most effective fertilization measures to stabilize crop yield in the black soil region. Nitrogen fertilizer, as a limiting factor for crop growth in the black soil region, should be emphasized in its application.

The Role of Algal Symbiont Growth in Driving the Thermal Responses of a Widespread Photosymbiotic Ciliate

Understanding the impacts of climate change on ecosystems remains a major contemporary research theme in the biosciences. However, the role of mixotrophs, organisms that combine autotrophic and heterotrophic processes to grow and reproduce, as important determinants of the thermal responses of ecosystems and their services is largely unresolved. In particular, photosymbioses, ubiquitous mixotrophic associations in which autotrophs reside within heterotrophic hosts, are known to play key roles in global biodiversity and carbon cycling. While specific impacts, particularly in the coral-zooxanthellae interaction, are thoroughly documented, ecologists lack a general theoretical framework describing the impacts of temperature change on photosymbiotic interactions. Here, I apply principles of the metabolic theory of ecology to assess the metabolic basis of the temperature-induced disruption of photosymbiosis in the microbial &lt;i&gt;Paramecium bursaria - Chlorella&lt;/i&gt; spp. association. In contrast to the general prediction that net autotrophy should decrease with temperature, this microbial photosymbiosis harboured larger algal symbiont populations and consumed fewer prey with warming, suggestive of increased net autotrophy with warming - a pattern that held across strains isolated from three different continents. This observation appeared to be a simple consequence of the response of symbiont growth rate. I conclude that a metabolic framework for photosymbiosis may prove insightful, but the ecological dynamics of the associations (e.g. mixotrophic strategy) must be considered in tandem.