FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.

[Detection of cytogenetic abnormalities in multiple myeloma by using optical genome mapping].

Multiple myeloma (MM) is a plasma cell neoplasm characterized by numerous chromosomal number and structural abnormalities, which are of great significance for risk stratification and response evaluation of MM patients. Optical genome mapping (OGM) is a novel technology that has the potential to resolve many of the issues and limitations associated with traditional cytogenetic methods. To date, the clinical utility of OGM has been validated in the fields of cancer, reproduction, and embryonic dysplasia, et al. In this study, we compared OGM to traditional techniques for the first time in five newly diagnosed MM patients, and evaluated the potential of OGM for detecting cytogenetic aberrations and its clinical application value in MM.

Th2 Cells Are Associated with Tumor Recurrence Following Radiation.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.

Bridging dose of U-100 glargine with first dose of insulin degludec improves glycaemia in the 48 h after transition in twice-daily glargine users.

AIMS: To study the effects of a bridging dose of U-100 glargine (U-100G) with the first dose of degludec in type 1 diabetes (T1D) patients transitioning from glargine to degludec, by comparing the glucose metrics 48 h before and after the transition. MATERIALS AND METHODS: Patients with T1D on a stable U-100G regimen and with glycated haemoglobin concentration <75 mmol/mol were randomized (double-blind) to one dose of placebo or U-100G with first dose of degludec, administered at 9:00 pm. Patients on once-daily U-100G at baseline received 50% of total U-100G dose (bridging dose), while patients on twice-daily U-100G received 50% of the evening U-100G dose. Participants wore a continuous glucose monitor during the study. RESULTS: Forty participants were randomized, of whom 37 completed the study. The cohort was 65% male, the mean age was 47 years, duration of T1D 22 years, BMI 26 kg/m2, HbA1c 51 mmol/mol and total daily insulin dose 0.7 units/kg body weight. The bridging group included 19 participants (once-daily U-100G: n = 12; twice-daily U-100G: n = 7) and the placebo group included 18 participants (once-daily U-100G: n = 12; twice-daily U-100G: n = 6). Change in time in range (TIR) was not significantly different between the two treatment groups. In secondary analyses, among twice-daily U-100G users, TIR (3.9-10 mmol/L) increased 8% in the bridging group in the 48 h after first dose of degludec compared to the preceding 48 h, while participants in the placebo group had a 9.5% decrease (p = 0.027). CONCLUSIONS: A subgroup of well-controlled twice-daily U-100G users transitioning to degludec benefited from a 50% bridging dose of evening U-100G with the first dose of degludec in a small pilot study.

Differential Association between Blood Glucose Levels and Nonrelapse Mortality after Allogeneic Hematopoietic Cell Transplantation Based on Presence or Absence of Preexisting Diabetes.

Malglycemia, defined as hyperglycemia, hypoglycemia, or increased glycemic variability, has been associated with increased mortality after allogeneic hematopoietic cell transplantation (HCT). Among critically ill non-HCT recipients with diabetes and poor glycemic control, compared to those without diabetes, stringent blood glucose control has been associated with increased mortality. This study investigated whether a pre-HCT diagnosis of diabetes and the type of pre-HCT diabetes treatment modulate the previously reported negative impact of malglycemia on post-HCT nonrelapse mortality (NRM). We performed a single-institution retrospective analysis of mortality outcomes after allogeneic HCT as a function of post-HCT blood glucose levels, pre-HCT diagnosis of diabetes, and type of pre-HCT diabetes treatment (insulin, no insulin). A total of 1062 patients who underwent allogeneic HCT between 2015 and 2020 were included in this study. Among these patients, 84 (8%) had a pre-HCT diagnosis of diabetes, of whom 38 (4%) used insulin and 46 (4%) used a noninsulin antiglycemic agent. Post-HCT blood glucose values measured within 100 days from HCT, modeled as a continuous nonlinear time-varying covariate, were associated with day-200 NRM, with both lower and higher glycemic values associated with higher NRM compared to normoglycemic values (adjusted P < .0001). The association between post-HCT blood glucose and NRM varied, however, depending on the presence or absence of a pre-HCT diagnosis of diabetes; that is, there was evidence of a statistical interaction between blood glucose levels and diabetes (adjusted P = .008). In particular, the detrimental impact of hyperglycemic values was more pronounced in patients without a pre-HCT diagnosis of diabetes compared to those with a pre-HCT diagnosis of diabetes. As reported previously, higher and lower blood glucose levels measured within 100 days after allogeneic HCT were associated with an increased risk of NRM; however, this association was more pronounced among patients without a pre-HCT diagnosis of diabetes compared to those with a pre-HCT diagnosis of diabetes, suggesting that patients with diabetes are relatively protected from the downstream effects of hyperglycemia. These data support the notion that patients with pre-HCT diabetes may need a different approach to blood glucose management after transplantation compared to those without diabetes. © 2024 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Deciphering the chemical profile and pharmacological mechanism of Jinlingzi powder against bile reflux gastritis using ultra-high performance liquid chromatography coupled with Q exactive focus mass spectrometry, network pharmacology, and molecular docking.

OBJECTIVE: To elucidate the chemical profile and the pharmacological mechanism by which Jinlingzi powder (, JLZP) treats bile reflux gastritis (BRG). METHODS: A BRG model was established in rats by oral administration of the model solution. JLZP was orally administered for 35 d. Residual gastric rate and tumor necrosis factor (TNF)-α, interleukin (IL)-6, and gastrin levels in the serum were measured, and stomach tissues were collected for histopathological analysis. We used ultra-high performance liquid chromatography coupled with Q Exactive Focus mass spectrometry to identify the chemical ingredients in JLZP. Then, protein-protein interaction and herb-compound-target networks were constructed to screen potential bioactive compounds and targets. Kyoto Encyclopedia of Genes and Genomes pathway analysis was then performed to elucidate the pathway involved in the JLZP-mediated treatment of BRG. After constructing the core compound-target-pathway interaction network, molecular docking was performed to study the binding free energy of core bioactive compounds and two candidate targets [RAC-alpha serine/threonine-protein kinase (AKT1) and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)]. RESULTS: JLZP extracts significantly promoted gastric emptying, regulating the release of cytokines (TNF-α and IL-6) and improving gastrin secretion and mucosal repair. Fifty-six compounds were tentatively characterized in JLZP. Moreover, the network pharmacology and molecular docking results showed that alkaloids and flavonoids might be the bioactive compounds in JLZP that treat BRG. JLZP might improve mucosal repair during BRG progression by modulating the phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B, hypoxia inducible factor-1, mitogen-activated protein kinase, forkhead box O, TNF, and IL-17 signaling pathways. CONCLUSIONS: We elucidated the chemical constituents and the pharmacological mechanism of JLZP in treating BRG and provided a basis for clinical application.

Bloodletting puncture in the treatment of acute ischemic stroke: protocol for a mixed-method study of a multi-center randomized controlled trial and focus group.

This study is to investigate the effectiveness and safety of bloodletting puncture (BP) for acute ischemic stroke (AIS) when used in combination with standard treatment, as well as the patients' feelings and attitudes toward the treatment. This is a mixed method research which includes a multi-center, superiority, randomized controlled clinical trial, and focus group interview. A total of 360 AIS participants will be enrolled. They will be randomized into one of the following two groups for 7 d: (a) BP with standard treatment group (n = 180); (b) standard treatment group (n = 180). The primary outcome will be National Institute of Health stroke scale (NIHSS) score at day 7 after treatment. Secondary outcomes will be changes of Glasgow Coma Scale score, NIHSS score, mRS and Traditional Chinese Medicine syndrome score from baseline to 7, 14, and 30 d after treatment, recurrence rate and all-cause mortality rate within 30 d, and the safety assessments. The focus group will be conducted with a purposive sample of 1-2 acupuncturists and 1-2 patients respectively at each center at 7 and 30 d after treatment. We designed a mixed method study to evaluate the effect of BP, an acupuncture therapy for patients with AIS. If the findings of this study confirm the effectiveness of BP to reduce the NIHSS score and other related outcomes and patients are willing to accept the therapy, we believe this study will help the implementation of this therapy in clinical practice, and provide new evidence for the treatment of AIS.

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.

INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid ß (Aß)1-42. METHODS: To create a model of AD, SH-SY5Y cells were treated with Aß1-42 and mice received intracerebroventricular injections of Aß1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aß and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aß expression was analyzed by immunofluorescence and histochemical examinations. RESULTS: Aß1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aß1-42, in which miR-146a upregulation increased the expression of Aß, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aß deposition and ROS accumulation via the p-p38 signaling pathway. CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aß deposition by triggering oxidative stress through activation of MAPK signaling.

Phase I dose escalation and expansion study of golidocitinib, a highly selective JAK1 inhibitor, in relapsed or refractory peripheral T-cell lymphomas.

BACKGROUND: Relapsed or refractory peripheral T-cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases that lack effective therapies. Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase I/II multinational study in patients with r/r PTCLs. PATIENTS AND METHODS: Patients with r/r PTCLs were eligible. The primary objectives were to assess safety and tolerability of golidocitinib and to define its recommended phase II dose (RP2D). The secondary objectives were to evaluate its antitumor activity and pharmacokinetics (PK). RESULTS: A total of 51 patients were enrolled and received golidocitinib treatment at 150 or 250 mg once daily (QD). The median prior lines of therapies were 2 (range: 1-8). Golidocitinib was tolerated at both doses tested, while a higher incidence of serious adverse events and dose modifications at 250 mg were observed. The most common grade ≥3 drug-related treatment-emergent adverse events were neutropenia (27.5%) and thrombocytopenia (11.8%). An objective response rate of 39.2% and a complete response rate of 21.6% were observed. With median follow-up time of 14.7 and 15.9 months, the median duration of response (DoR) and progression-free survival were 8.0 and 3.3 months, respectively. Based on these data, 150 mg QD was defined as the RP2D. Golidocitinib demonstrated a favorable PK profile as an oral agent. Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib. CONCLUSIONS: In this phase I study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pretreated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs.

TRAF2/3 deficient B cells resist DNA damage-induced apoptosis via NF-κB2/XIAP/cIAP2 axis and IAP antagonist sensitizes mutant lymphomas to chemotherapeutic drugs.

Deletion of TRAF2 or TRAF3 in B cells prolongs their survival. However, it remains unknown whether deletion of such factors affects B cells' ability to tolerate DNA damage, which can be induced by chemotherapeutics and cause apoptosis. Genetic alterations of TRAF2 or TRAF3 are observed in subsets of human B-cell lymphomas and B cell-specific deletion of TRAF3 led to lymphoma development in aged mice. However, it remains unknown whether double deficiency of TRAF2 and TRAF3 accelerates B-cell lymphomagenesis. Here, we showed that B cell-specific TRAF2/3 double deficient (B-TRAF2/3-DKO) B cells were remarkably more resistant to DNA damage-induced apoptosis via upregulating cIAP2 and XIAP, which in turn attenuates caspase-3 activation. Mechanistically, resistance to DNA damage-induced apoptosis required NF-κB2, which effects by upregulating XIAP and cIAP2 transcription. B-TRAF2/3-DKO mice exhibited a shorter lifespan and succumbed to splenomegaly and lymphadenopathy. Unexpectedly, the incidence of B-cell lymphoma development in B-TRAF2/3-DKO mice was relatively rare (∼10%). Sequencing B cell receptor repertoire of diseased B cells revealed that TRAF2/3 deficiency caused abnormal oligoclonal or clonal expansion of B cells. While a fraction of mutant B cells (25-43%) from aged diseased mice harbored recurrent chromosomal translocations, primary B cells isolated from young B-TRAF2/3-DKO mice had no detectable chromosomal alterations, suggesting that TRAF2/3 deficiency per se does not cause evident genomic instability in B cells. Chemo-resistant TRAF3-deficient B-cell lymphomas were sensitized to chemotherapeutic drugs by blocking IAP activity using IAP antagonist. We conclude that double deficiency of TRAF2 and TRAF3 does not accelerate B-cell lymphomagenesis. Our studies provide insight into mechanisms regulating DNA damage-induced apoptosis and may help develop effective therapies targeting mutant B-cell lymphomas using IAP antagonist.

miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signalingmi / R-146a empeora el deterioro cognitivo y la patología tipo Alzheimer al promover el estrés oxidativo a través de la vía de señalización MAPK

Introduction: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1–42. Methods: To create a model of AD, SH-SY5Y cells were treated with Aβ1–42 and mice received intracerebroventricular injections of Aβ1–42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations. Results: Aβ1–42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1–42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway. Conclusions: Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.(AU)

Introducción: miR-146a-5p es un elemento regulador clave en la respuesta inmune. Sin embargo, estudios recientes sugieren que miR-146a-5p también está involucrado en el desarrollo de la enfermedad de Alzheimer (EA), aunque aún no se conoce con exactitud el mecanismo por el que esto sucede. Analizamos los efectos de miR-146a en un modelo animal y en células SH-SY5Y expuestas a β-amiloide (Aβ)1-42. Métodos: Tratamos células SH-SY5Y con Aβ1-42 e inyectamos Aβ1-42 en los ventrículos cerebrales de ratones para generar un modelo celular y otro animal de EA. Estimamos los niveles transcripcionales de miR-146a mediante PCR en tiempo real. Al mismo tiempo, transfectamos temporalmente las células y los ratones con imitador/inhibidor de miR-146a-5p para evaluar el papel de miR-146a. Estudiamos el papel de algunas vías de señalización, como la de p38, y los niveles de especies reactivas de oxígeno (ERO) con inhibidores específicos. Los niveles de Aβ y de proteína precursora amiloidea (APP) se determinaron con inmunoblot. También se analizó la expresión de Aβ mediante inmunofluorescencia y análisis histoquímico. Resultados: Las células SH-SY5Y expuestas a Aβ1-42 mostraron altos niveles transcripcionales de miR-146a y APP. La vía de señalización p-38 MAPK y la producción de EROs se activaron al utilizar un imitador de miR-146a-5p. Sin embargo, el bloqueo de miR-146a-5p con un inhibidor redujo los niveles de APP, EROs y p-p38 MAPK. Se observó un fenómeno similar en los ratones tratados con Aβ1-42: la sobrerregulación de miR-146a aumentó la expresión de Aβ, p-p38 y EROs, mientras que la inhibición de miR-146a tuvo el efecto contrario. Esto sugiere que miR-146a está involucrado en el aumento de acumulación de Aβ y de producción de EROs por medio de la vía de señalización p-p38. Conclusiones: Nuestro estudio muestra que miR146a-5p aumenta la acumulación de Aβ al promover el estrés oxidativo a través de la activación de la vía de señalización MAPK.(AU)

[Diagnostic and prognostic values of flow cytometry in diffuse large B-cell lymphoma with bone marrow involvement].

Objective: To analyze the diagnostic and prognostic values of flow cytometry (FC) in diffuse large B cell lymphoma (DLBCL) with bone marrow involvement (BMI). Methods: The clinical data of 412 patients with newly diagnosed DLBCL, including 243 males and 169 females, aged 64 (28-92) years old, in the Department of Hematology at Peking University Third Hospital from December 2012 to June 2022 were retrospectively analyzed. All patients underwent bone marrow biopsy (BMB) and bone marrow FC. The patients with BMI by FC were further detected by fluorescence in situ hybridization (FISH) for gene analysis. The positive rates and consistency of BMI detected by BMB and FC were evaluated. According to the results of BMB and FC examinations, all patients were divided into four groups: the BMB+FC+group (115 cases), the BMB-FC+group (50 cases), the BMB+FC-group (8 cases, the results did not include in statistical analysis because of small sample size), and the BMB-FC-group (239 cases). The clinical features, treatment response rates, 5-year survival rates, and immunophenotype characteristics by FC in different groups were analyzed. Results: Among the 412 patients with DLBCL, the positivity rates of BMB and FC for BMI detection were 29.9% (123/412) and 40.0% (165/412), respectively. Good consistency between BMB and FC was found (Kappa=0.841, P=0.001). The numbers of extranodal involvement≥2, splenomegaly, huge mass, higher Ki-67 score, higher international prognostic index (IPI) score, thrombocytopenia, and elevated lactate dehydrogenase level were more prevalent in the BMB+FC+group than those in the BMB-FC+group and the BMB-FC-group (all P<0.05). The treatment response rate in BMB+FC+group was 63.5% (73/115), which was lower than those in BMB-FC+group (88.0%, 44/50, P=0.048) and BMB-FC-group (90.0%, 215/239, P=0.032), respectively. The 5-year overall survival rates in three groups were (53.6±9.7) %, (72.5±8.6) %, and (75.2±7.6) %, respectively, with a statistically significant difference (P=0.037). According to the FISH results of bone marrow, 102 cases were diagnosed as not otherwise specified (NOS), 48 cases were diagnosed as double hit lymphoma (DHL), and 15 cases were diagnosed as triple hit lymphoma (THL). Compared with NOS subtypes, the tumor cells in DHL or THL subtypes had higher proportion of increased side scatter (SSC), higher positive rates of CD10 expression, CD38 strong expression and CD56 expression, and lower proportion of surface immunoglobulin light chain restriction (all P<0.05). Conclusions: FC is well consistent with BMB in diagnosing DLBCL with BMI. Combined with FISH detection, FC can contribute to the auxiliary diagnosis and risk stratification for DHL and THL, and provide reference for the prognostic evaluation in DLBCL with BMI.

[Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for T lymphoblastic leukemia/lymphoma].

Objective: To analyze the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating T lymphoblastic leukemia/lymphoma (T-ALL/LBL) . Methods: This study retrospectively evaluated 119 adolescent and adult patients with T-ALL/LBL from January 2006 to January 2020 at Peking University Third Hospital and Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Patients were divided into chemotherapy-only, chemotherapy followed by allo-HSCT, and chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) groups according to the consolidation regimen, and the 5-year overall survival (OS) and progression-free survival (PFS) rates of each group were compared. Results: Among 113 patients with effective follow-up, 96 (84.9%) patients achieved overall response (ORR), with 79 (69.9%) having complete response (CR) and 17 (15.0%) having partial response (PR), until July 2022. The analysis of the 96 ORR population revealed that patients without transplantation demonstrated poorer outcomes compared with the allo-HSCT group (5-year OS: 11.4% vs 55.6%, P=0.001; 5-year PFS: 8.9% vs 54.2%, P<0.001). No difference was found in 5-year OS and 5-year PFS between the allo-HSCT and auto-HSCT groups (P=0.271, P=0.197). The same results were achieved in the CR population. Allo-HSCT got better 5-year OS (37.5% vs 0) for the 17 PR cases (P=0.064). Different donor sources did not affect 5-year OS, with sibling of 61.1% vs hap-haploidentical of 63.6% vs unrelated donor of 50.0% (P>0.05). No significant difference was found in the treatment response in the early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP) and non-ETP populations. The ETP group demonstrated lower 5-year OS compared with the non-ETP group in the chemotherapy alone group (0 vs 12.6%, P=0.045), whereas no significant difference was found between the ETP and non-ETP groups in the allo-HSCT group (75.0% vs 62.9%, P=0.852). Multivariate analysis revealed that high serum lactate dehydrogenase level, without transplantation, and no CR after chemotherapy induction were independently associated with inferior outcomes (P<0.05) . Conclusion: Allo-HSCT could be an effective consolidation therapy for adult and adolescent patients with T-ALL/LBL. Different donor sources did not affect survival. Allo-HSCT may overcome the adverse influence of ETP-ALL/LBL on OS.

[Clinical features and prognostic factors of elderly patients with mantle cell lymphoma].

Objective: To examine the clinical characteristics and prognostic factors of elderly patients with mantle cell lymphoma (MCL) and the impact of nutrition and underlying diseases on the prognosis of elderly patients with MCL. Methods: retrospectively analyzed 255 elderly patients with MCL from 11 medical centers, including Peking University Third Hospital between January 2000 and February 2021. We analyzed clinical data, such as age, gender, Mantle Cell Lymphoma International Prognostic Index score, and treatment options, and performed univariate and multivariate prognostic analysis. We performed a comprehensive geriatric assessment on elderly MCL patients with medical records that included retraceable underlying disease and albumin levels, and we investigated the impact of basic nutrition and underlying disorders on MCL prognosis in the elderly. Results: There were 255 senior individuals among the 795 MCL patients. Elderly MCL was more common in males (78.4%), with a median age of 69 yr (ages 65-88), and the majority (88.6%) were identified at a late stage. The 3-yr overall survival (OS) rate was 42.0%, with a 21.2% progression-free survival (PFS) rate. The overall response rate (ORR) was 77.3%, with a 33.3% total remission rate. Elderly patients were more likely than younger patients to have persistent underlying illnesses, such as hypertension. Multivariate analysis revealed that variables related with poor PFS included age of ≥80 (P=0.021), Ann Arbor stage Ⅲ-Ⅳ (P=0.003), high LDH level (P=0.003), involvement of bone marrow (P=0.014). Age of ≥80 (P=0.001) and a high LDH level (P=0.003) were risk factors for OS. The complete geriatric assessment revealed that renal deficiency was associated with poorer OS (P=0.047) . Conclusions: Elderly MCL patients had greater comorbidities. Age, LDH, renal function, bone marrow involvement, and Ann Arbor stage are all independent risk factors for MCL in the elderly.

[Investigation on medical security and quality of life of migrant workers with pneumoconiosis].

Objective: To investigate and understand the medical security and quality of life of migrant workers with pneumoconiosis, so as to provide scientific basis for the prevention and control countermeasures of migrant workers with pneumoconiosis and targeted poverty alleviation. Methods: Using a stratified random sampling method, 200 migrant workers diagnosed with pneumoconiosis at the Shandong Academy of Occupational Health and Occupational Medicine from January 2016 to December 2021 were selected as the observation group, while 200 non migrant workers diagnosed with pneumoconiosis were selected as the control group. St. George's Respiratory Questionnaire (SGRQ) and Pneumoconiosis Questionnaire were used to collect and compare information on the age, working age of dust exposure, economic sources, employment status, income, medical security and quality of life of two groups of patients. Results: The age of migrant worker pneumoconiosis patients in the observation group was (58.1±8.1) years old, and the working age of dust exposure was (19.3±10.1) years. The main source of income was children support (85.5%, 171/200), employment status was mainly wait for employment or unemployed (69.0%, 138/200), personal monthly income was mainly non income (90.0%, 180/200), and family annual income was mainly less than 10000 yuan (48.0%, 96/200). The average personal annual medical expenditure of 5000-<10000 yuan accounted for 42.0% (84/200). The age of pneumoconiosis patients in the control group was (59.2±8.9) years old, and the working age of dust exposure was (20.2±10.5) years. The main source of income was retirement pension or salary (99.0%, 198/200), with retirement as the main employment status (66.0%, 132/200), the main personal monthly income was 2000-<4000 yuan (61.5%, 123/200), the main family annual income was 20000-<40000 yuan (44.0%, 88/200), and the average personal annual medical expenditure was mostly non-expenditure (92.0%, 184/200). There were statistically significant differences in the distribution of economic sources, employment status, personal monthly income, family annual income and average personal annual medical expenditure between the two groups (P<0.001). The main type of insurance for the observation group was rural cooperative medical care (68.5%, 137/200), and 87.0% (174/200) had no medical reimbursement and a proportion less than 50%. There were statistically significant differences in insurance type and medical reimbursement proportion between the two groups (P<0.001). The respiratory symptoms, activity ability, daily life influence and total quality of life scores of pneumoconiosis patients in the observation group were significantly higher than those in the control group, the differences were statistically significant (P<0.001) . Conclusion: Migrant workers with pneumoconiosis have low income, high medical expenditure, low medical reimbursement proportion and poor quality of life. Therefore, it is necessary to draw high attention from relevant departments and provide timely attention and assistance to improve the quality of life of migrant workers with pneumoconiosis.

Inducible nitric oxide synthase (iNOS)-activated Cxcr2 signaling in myeloid cells promotes TGFß-dependent squamous cell carcinoma lung metastasis.

Transforming growth factor beta (TGFß) activity is linked to metastasis in many cancer types, but whether TGFß activity is necessary for squamous cell carcinoma (SCC) lung metastasis has not been studied. Here we used a lung metastatic SCC model derived from keratin 15 (K15). KrasG12D.Smad4-/- SCC and human SCC specimens to identify metastasis drivers and test therapeutic interventions. We demonstrated that a TGFß receptor (TGFßR) inhibitor reduced lung metastasis in mouse SCC correlating with reduced CD11b+/Ly6G+ myeloid cells positive for inducible nitric oxide synthase (iNOS). Further, TGFß activity and iNOS were higher in primary human oral SCCs with metastasis than SCCs without metastasis. Consistently, either depleting myeloid cells with anti-Gr1 antibody or inhibiting iNOS with L-N6-(1-iminoethyl)-l-lysine (L-NIL) reduced SCC lung metastasis. L-NIL treated tumor-bearing mice exhibited reductions in tumor-infiltrating myeloid cells and in plasma Cxcl5 levels, and attenuated primary tumor growth with increased apoptosis and decreased proliferation. Blocking Cxcl5 with an antagonist of its receptor Cxcr2, SB225002, also reduced SCC lung metastasis.

The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma.

BACKGROUND: The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. METHODS: We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1-ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti-PD-L1, and anti-signal transducer and activator of transcription 3 (STAT3) in vivo. RESULTS: PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. CONCLUSIONS: Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell-invasive properties.

[Association between muscle mass and quality of life in Shaanxi adults].

Objective: To investigate the association between muscle mass and quality of life in adults in Shaanxi adults. Methods: The data in this analysis were part of the baseline survey of the Regional Ethnic Cohort Study in Northwest China from June 2018 to May 2019 in Shaanxi Province. The participants' quality of life, including physical component summary (PCS) and mental component summary (MCS), was assessed by the 12-Item Short Form Survey, and the Body Fat Determination System measured muscle mass. A logistic regression model with adjustment for confounding factors was established to analyze the association between muscle mass and quality of life in different genders. Further, sensitivity and subgroup analyses were conducted to explore its stability. Finally, a restricted cubic spline was employed to investigate the dose-response relationship between muscle mass and quality of life in different genders. Results: A total of 20 595 participants were included, with an average age of 55.0, and 33.4% were male. After controlling for potential confounders, compared with the Q1 group, the risk of low PCS was reduced by 20.6% (OR=0.794, 95%CI: 0.681-0.925) and the risk of low MCS was lower reduced by 20.1% (OR=0.799, 95%CI: 0.689-0.926) in female Q5 groups. Compared with the Q1 group, the risk of low PCS was reduced by 24.4% (OR=0.756, 95%CI: 0.644-0.888) in the male Q2 group. However, no significant association between muscle mass and MCS in males has been found. In females, restricted cubic spline analysis showed a significant linear dose-response relationship between muscle mass and PCS and MCS. Conclusions: There is a positive association between muscle mass and quality of life in Shaanxi adults, especially females. With the increase in muscle mass, the physical and mental functions of the population continue to improve.

Host-specific differences in top-expanded TCR clonotypes correlate with divergent outcomes of anti-PD-L1 treatment in responders versus non-responders.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the responses to ICI treatment are highly variable in different individuals and the underlying mechanisms remain poorly understood. Here, we employed a mouse squamous cell carcinoma (SCC) model where tumor-bearing recipients diverged into responders (R) versus non-responders (NR) upon anti-PD-L1 treatment. We performed in-depth TCRß sequencing with immunoSEQ platform to delineate the differences in CD8 tumor-infiltrating lymphocytes (TILs). We found that R and NR CD8 TILs both exhibited evidence of clonal expansion, suggesting activation regardless of response status. We detected no differences in clonal expansion or clonal diversity indexes between R vs. NR. However, the top expanded (>1%) TCRß clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, showing a preferential expansion of distinct TCRß clonotypes in response to the same SCC tumor in R vs. NR. Notably, the mutual exclusivity of TCR clonotypes in R vs. NR was only observed when top TCRß clonotypes were counted, because such top-expanded clonotypes are present in the opposite outcome group at a much lower frequency. Many TCRß sequences were detected in only one recipient at a high frequency, implicating highly individualized anti-tumor immune responses. We conclude that differences in the clonal frequency of top TCR clonotypes between R and NR CD8 TILs may be one of the factors underlying differential anti-PD-L1 responses. This notion may offer a novel explanation for variable ICI responses in different individuals, which may substantially impact the development of new strategies for personalized cancer immunotherapy.