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The paper provides the issues regarding the body composition change by sodium-glucose cotransporter 2 inhibitors.The paper provides the issues regarding the body composition change by sodium-glucose cotransporter 2 inhibitors.

The dynamics in polymeric systems affect various important properties including mechanical and thermal behaviors, and extensive studies in this field have been executed not only academically but also practically [...]

Aims/Introduction It is unclear how changes in body composition induced by sodium–glucose cotransporter 2 (SGLT2) inhibitor treatment correlate with metabolic profile changes. We aimed to clarify how metabolic profile changes correlate with body component changes, and if SGLT2 inhibitor treatment causes sarcopenia and bone mineral content (BMC) loss. Materials and Methods Moderately obese Japanese type 2 diabetes patients, treated with luseogliflozin for a year, were observed prospectively and evaluated for body composition changes. We analyzed the changes in the individual body components during treatment, and their correlation with other clinical variables. Results The efficacy analysis set comprised 37 of 43 enrolled patients. The total fat mass significantly decreased early in the treatment at and after week 4, with a mean decrease of −1.97 kg (95% confidence interval −2.66 to −1.28) at week 24. The visceral fat area at week 24 showed an average downward trend, although this was not significant. The changes in visceral fat area in individual patients showed a significant negative correlation with the extent of the baseline visceral fat area (r = −0.399, P = 0.023). The skeletal muscle mass index showed a significant but small change at and after week 36. The BMC profile showed a transient significant decrease only at week 12. No significant change in BMC was noted at other time‐points. Conclusions Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction. Luseogliflozin treatment was found to be capable of controlling T2D with favorable changes in the body composition and metabolism accompanied by minimal muscle and BMC reduction, even in moderately obese patients. The changes in the visceral fat area at Week 24 in individual patients showed a significant negative correlation with the respective visceral fat area levels at the baseline (r = −0.457, P = 0.0085).

Pancreatic cancer is an aggressive, solid tumor, with a grave prognosis. Despite surgical treatment in patients with pancreatic cancer, the rate of recurrence is high. In addition, although tumor biomarkers are frequently used to confirm advanced pancreatic cancer, this is not accurate and the biomarkers currently used cannot indicate prognosis. This study sought to evaluate circulating tumor DNA as a tumor biomarker to prognosticate pancreatic cancer. Patients with advanced pancreatic cancer and liver metastasis (N = 104) were included, and blood samples were collected from all patients. The mutant allele frequency was measured using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with > 240 hot spots. In patients with advanced pancreatic cancer, 50% (N = 52) had detectable ctDNA levels, with TP53 (45%, N = 47) and KRAS (42.3%, N = 44) mutations the most common. Patients with detectable circulating tumor DNA levels also had significantly worse overall survival and progression free survival than ctDNA negative patients (8.4 vs 16 months, P<0.0001 for overall survival; 3.2 vs 7.9 months, P<0.0001 for progression-free survival). In a multivariate analysis, ctDNA status was independently associated with overall survival and progression-free survival (HR = 3.1, 95%CI = 1.9-5.0, P<0.0001; HR 2.6, 95%CI = 1.7-4.0, P<0.0001, respectively). Moreover, circulating tumor DNA significantly correlated with a higher number of liver metastases, the presence of lung and/or peritoneal metastases, tumor burden, and higher carbohydrate antigen 19-9 levels. This study supports the use of circulating tumor DNA as an independent prognostic marker for advanced pancreatic cancer.

Background Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC. Methods In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. Results Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension ( n  = 10 [38.5%]), proteinuria ( n  = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. Conclusions Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. Trial registration ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.

To assess the relationship between polydoctoring and patient outcomes, we conducted a retrospective cohort study using a Japanese population-based dataset from April 2014 to December 2022. Overall, 2,338,965 patients aged 75–89 years with at least two chronic conditions were included. Polydoctoring was assessed by the number of regularly visited facilities (RVFs). The primary outcome was all-cause mortality, with secondary outcomes being all-cause hospitalizations, hospitalizations for ambulatory care-sensitive conditions (ACSCs), and outpatient costs. During the study period, 14.5% of participants died, 52.2% were hospitalized, and 12.5% experienced ACSC-related hospitalizations. Patients without RVFs had the highest mortality risk (HR: 3.23, 95% CI: 3.14–3.33), while those with ≥ 5 RVFs had the lowest (HR: 0.67, 95% CI: 0.62–0.73). ACSC-related hospitalizations were U-shaped, with increased risk at ≥ 5 RVFs (HR: 1.13, 95% CI: 1.06–1.22). Outpatient costs increased 3.21 times for ≥ 5 RVFs compared to 1 RVF. Polydoctoring was associated with reduced mortality but higher hospitalization rates and costs, with an optimal RVF range of 2–3 which minimized ACSC-related admissions. These findings emphasize the need for strategies that balance the benefits and costs of polydoctoring to support sustainable healthcare through improved care coordination and resource management for aging populations.

The release of Ca 2+ from the sarcoplasmic reticulum into the cytoplasm, followed by its reuptake by sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), is critical for the muscle contraction-relaxation cycle. In this study, we identify a small transmembrane protein, predominantly expressed in fast-twitch muscles, which regulates SERCA1 activity. This protein, termed muscle-enriched Ca 2+ regulator (MCARE), enhances SERCA1 function by competitively inhibiting myoregulin, a muscle-specific micropeptide that otherwise suppresses SERCA1 activity. By facilitating more efficient Ca 2+ clearance from the cytoplasm, MCARE accelerates muscle relaxation. Mcare -deficient mice exhibit symptoms resembling muscular dystrophy, including progressive muscle wasting in fast-twitch muscles, reduced muscle strength, and increased susceptibility to exercise-induced muscle damage. Notably, these mice also present with distinctive rippling muscle contractions. Our findings establish MCARE as a key regulator of SERCA1 activity, essential for maintaining Ca 2+ homeostasis and the functional integrity of fast-twitch muscle fibers. The study reveals that MCARE, a previously uncharacterized muscle protein, controls calcium handling and contraction in skeletal muscle, and its absence leads to impaired muscle function in mice.

To improve radiotherapy, especially that with ion beams such as proton and carbon ion beams, the mechanisms of interactions induced by ionizing radiation must be understood. MPEXS2.1-DNA is a Monte Carlo simulation code developed for water radiolysis studies and DNA damage simulations that uses GPU devices for fast computation. However, the original chemistry model in MPEXS2.1-DNA did not include detailed chemical reactions for reactive oxygen species (ROS), e.g., O •- , O 2 , O 2 •- , HO 2 • , HO 2 - . In the present study, drawing the former work on the step-by-step (SBS) model for the RITRACKS code, we implemented an alternative SBS model into MPEXS2.1-DNA to increase the capabilities and computational speed of water radiolysis simulations under ion irradiation. This model is based on the theory of Green’s function of the diffusion equation (GFDE-SBS). Also, we implemented multiple ionization processes which enhance ROS generation under high-LET irradiation. We compared the simulation results obtained by GFDE-SBS with experimental data from previous studies. The validation results demonstrated that the GFDE-SBS model accurately reproduced the measured radiation chemical yields of major species, such as hydroxyl radicals and hydrogen peroxide. Furthermore, the computational speed of GFDE-SBS was increased approximately ten times faster than the original model due to the changes in time stepping. Additionally, simulations using a Fricke dosimeter confirmed that this model is reliable for long-term simulations over seconds. These improvements enable simulations of radiation interactions and can help in the study of DNA damage mechanisms.

BackgroundElderly pancreatic cancer (PC) patients are often considered vulnerable to treatment and standard treatment strategy for this subpopulation is uncertain. Cachexia and sarcopenia are reported to be associated with reduced physical performance, reduced anti-tumor response, increased chemotherapy toxicity, and poor prognosis in several malignancies. The aim of this study was to evaluate the impact of cachexia and sarcopenia on the clinical course of elderly PC patients receiving chemotherapy.MethodsWe retrospectively investigated consecutive elderly metastatic PC patients (≥ 75 years) treated with chemotherapy at our institution between January 2015 and April 2020. Skeletal muscle index was calculated at the third lumbar vertebra using pretreatment computed tomography. We evaluated time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), early treatment discontinuation, relative dose intensity (RDI), and severe adverse events (AEs).ResultsAmong 80 patients included (gemcitabine plus nab-paclitaxel [GnP] 52; gemcitabine 21; S1 6; modified FOLFIRINOX 1), cachexia and sarcopenia were present in 48 (60%) and 61 (76%) patients, respectively. Cachexia was associated with older age, worse performance status, higher level of neutrophil to lymphocyte ratio, worse nutritional status, and shorter TTF and PFS. Furthermore, it was also associated with early treatment discontinuation, reduced RDI of nab-paclitaxel, and increased incidence of grade 4 neutropenia in patients receiving GnP. On the other hand, sarcopenia had less impact on the clinical course of elderly PC patients.ConclusionsIn our experience, cachexia was considered an effective tool in the management of elderly PC patients receiving palliative chemotherapy.

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs. Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.