Advances in molecular-targeted therapy for unresectable pancreatic cancer / 临床肝胆病杂志

Pancreatic cancer is one of the most prevalent malignant tumors of the digestive system， and its incidence and mortality rates are increasing year by year. Most patients with pancreatic cancer are unable to receive surgery due to the advanced stage. Although chemotherapy regimens based on gemcitabine and fluorouracil have prolonged the survival time of patients to some extent， some patients cannot tolerate chemotherapy and hence lose the opportunity for treatment. With the advent of the era of precision medicine， molecular-targeted therapy has exhibited an excellent therapeutic efficacy and has thus become one of the most important treatment techniques for tumors； however， due to the high heterogeneity of pancreatic cancer and its complicated tumor microenvironment， molecular-targeted therapy for pancreatic cancer has not achieved notable results. Therefore， it is imperative to seek new therapeutic targets and medications to overcome this issue. This article reviews the latest advances in the research on molecular-targeted therapy for unresectable pancreatic cancer based on common molecular targets and tumor immunity-related therapeutic targets， in order to provide new treatment strategies for patients with pancreatic cancer.

A molecular approach to triple-negative breast cancer: targeting the Notch signaling pathway

ABSTRACT Introduction Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This phenotype renders triple-negative breast cancer cells refractory to conventional therapies, resulting in poor clinical outcomes and an urgent need for novel therapeutic approaches. Recent studies have implicated dysregulation of the Notch receptor signaling pathway in the development and progression of triple-negative breast cancer. Objective This study aimed to conduct a comprehensive literature review to identify potential therapeutic targets of the Notch pathway. Our analysis focused on the upstream and downstream components of this pathway to identify potential therapeutic targets. Results Modulating the Notch signaling pathway may represent a promising therapeutic strategy to treat triple-negative breast cancer. Several potential therapeutic targets within this pathway are in the early stages of development, including upstream (such as Notch ligands) and downstream (including specific molecules involved in triple-negative breast cancer growth). These targets represent potential avenues for therapeutic intervention in triple-negative breast cancer. Comments Additional research specifically addressing issues related to toxicity and improving drug delivery methods is critical for the successful translation of these potential therapeutic targets into effective treatments for patients with triple-negative breast cancer.

Seguridad de las drogas biológicas y sintéticas dirigidas utilizadas en pacientes con enfermedades reumáticas inmunomediadas. Datos del registro BIOBADASAR 3.0 / Safety of biological and targeted synthetic drugs in patients with immune-mediated rheumatic diseases. Data from the BIOBADASAR 3.0 registry

Introducción: conocer la seguridad de las drogas actualmente disponibles para el tratamiento de las enfermedades reumáticas es muy importante al momento de tomar decisiones terapéuticas objetivas e individualizadas en la consulta médica diaria. Asimismo, datos de la vida real amplían el conocimiento revelado por los ensayos clínicos. Objetivos: describir los eventos adversos (EA) reportados, estimar su frecuencia e identificar los factores relacionados con su desarrollo. Materiales y métodos: se utilizaron datos BIOBADASAR, un registro voluntario y prospectivo de seguimiento de EA de tratamientos biológicos y sintéticos dirigidos en pacientes con enfermedades reumáticas inmunomediadas. Los pacientes son seguidos hasta la muerte, pérdida de seguimiento o retiro del consentimiento informado. Para este análisis se extrajeron datos recopilados hasta el 31 de enero de 2023. Resultados: se incluyó un total de 6253 pacientes, los cuales aportaron 9533 ciclos de tratamiento, incluyendo 3647 (38,3%) ciclos sin drogas modificadoras de la enfermedad biológicas y sintéticas dirigidas (DME-b/sd) y 5886 (61,7%) con DME-b/sd. Dentro de estos últimos, los más utilizados fueron los inhibidores de TNF y abatacept. Se reportaron 5890 EA en un total de 2701 tratamientos (844 y 1857 sin y con DME-b/sd, respectivamente), con una incidencia de 53,9 eventos cada 1000 pacientes/año (IC 95% 51,9-55,9). La misma fue mayor en los ciclos con DME-b/sd (71,1 eventos cada 1000 pacientes/año, IC 95% 70,7-77,5 versus 33,7, IC 95% 31,5-36,1; p<0,001). Las infecciones, particularmente las de la vía aérea superior, fueron los EA más frecuentes en ambos grupos. El 10,9% fue serio y el 1,1% provocó la muerte del paciente. El 18,7% de los ciclos con DME-b/sd fue discontinuado a causa de un EA significativamente mayor a lo reportado en el otro grupo (11,5%; p<0,001). En el análisis ajustado, las DME-b/sd se asociaron a mayor riesgo de presentar al menos un EA (HR 1,82, IC 95% 1,64-1,96). De igual manera, la mayor edad, el mayor tiempo de evolución, el antecedente de enfermedad pulmonar obstructiva crónica, el diagnóstico de lupus eritematoso sistémico y el uso de corticoides se asociaron a mayor riesgo de EA. Conclusiones: la incidencia de EA fue significativamente superior durante los ciclos de tratamientos que incluían DME-b/sd.

Introduction: knowing the efficacy and safety of the drugs currently available for the treatment of rheumatic diseases is very important when making objective and individualized therapeutic decisions in daily medical consultation. Likewise, real-life data extends the knowledge revealed by clinical trials. Objectives: to describe the reported adverse events (AEs), estimate their frequency and identify factors associated to them. Materials and methods: BIOBADASAR data were used, which is a voluntary, prospective follow-up registry of AEs of biological and synthetic treatments in patients with immune-mediated rheumatic diseases. Patients are followed until death, loss of followup, or withdrawal of informed consent. To carry out this analysis, the data collected up to January 31, 2023 was extracted. Results: a total of 6253 patients were included, who contributed with 9533 treatment periods, including 3647 (38.3%) periods without b/ts-DMARDs and 5886 (61.7%) with b/ts-DMARDs. Among the latter, the most used were TNF inhibitors and abatacept. A total of 5890 AEs were reported in a total of 2701 treatments (844 and 1857 without and with b/ts-DMARDs, respectively), with an incidence of 53.9 events per 1000 patients/ year (95% CI 51.9-55.9). It was higher during the periods with b/ts-DMARDs (71.1 events per 1000 patients/year, 95% CI 70.7-77.5 vs 33.7, 95% CI 31.5-36.1, p<0.001). Infections, particularly those of the upper respiratory tract, were the most frequent AEs in both groups. 10.9% were severe and 1.1% were associated with the death of the patient. 18.7% of the periods with b/ts-DMARDs were discontinued due to an AE, significantly higher than that reported in the other group (11.5%; p<0.001). In the adjusted analysis, b/ts-DMARDs were associated with a higher risk of presenting at least one AE (HR 1.82, 95% CI 1.64-1.96). Similarly, older age, longer evolution time, history of chronic obstructive pulmonary disease, diagnosis of systemic lupus erythematosus, and use of corticosteroids were associated with a higher risk of AE. Conclusions: the incidence of AEs was significantly higher during those treatment periods that included DME-b/sd.

Advances in macrophage-targeting nanoparticles for the diagnosis and treatment of inflammatory bowel disease / 浙江大学学报·医学版

The pathogenesis of inflammatory bowel disease (IBD) is not fully elucidated. However, it has been considered that inflammatory macrophages may be involved in the imbalance of the intestinal mucosal immunity to regulate several signaling pathways, leading to IBD progression. The ratio of M1 to M2 subtypes of activated macrophages tends to increase in the inflamed intestinal section. There are challenges in the diagnosis and treatment of IBD, such as unsatisfactory specificity of imaging findings, low drug accumulation in the intestinal lesions, unstable therapeutic efficacy, and drug-related systemic toxicity. Recently developed nanoparticles may provide a new approach for the diagnosis and treatment of IBD. Nanoparticles targeted to macrophages can be used as contrast agents to improve the imaging quality or used as a drug delivery vector to increase the therapeutic efficiency of IBD. This article reviews the research progress on macrophage-targeting nanoparticles for the diagnosis and treatment of IBD to provide a reference for further research and clinical application.

Value of normalized apparent diffusion coefficient in predicting HER2 expression in bladder cancer / 现代泌尿外科杂志

【Objective】 To predict the expression of human epidermal growth factor receptor 2 (HER2) in urothelial bladder carcinoma based on normalized apparent diffusion coefficient (ADC). 【Methods】 The preoperative pelvic 3.0T magnetic resonance imaging (MRI) images of 127 patients with urothelial bladder carcinoma were retrospectively studied, the ADC was measured, and the HER2 expression in postoperative tissue specimens was determined with immunohistochemistry (IHC). The differences in normalized ADC were analyzed among different HER2 expressions and among different expression divisions. Correlation between normalized ADC and HER2 expression was analyzed. The optimal diagnostic threshold for distinguishing different expression divisions were determined with receiver operating characteristic (ROC) curve. 【Results】 Normalized ADC was negatively correlated with HER2 expression (tau-b=-0.180, P=0.008). Normalized ADC of HER2 overexpression group (IHC 2+, 3+) was lower than that of HER2 negative group (IHC 0, 1+) (P=0.081). Normalized ADC of HER2 expression group (IHC 1+, 2+, 3+) was significantly lower than that of HER2 zero-expression group (IHC 0) (P=0.020). Normalized ADC of HER2 strong positive group (IHC 3+) was significantly lower than that of HER2 non-strong positive group (IHC 0, 1+, 2+) (P=0.024). The optimal diagnostic threshold of HER2 strong positive group was 0.849; the sensitivity, specificity and accuracy were 0.621, 0.909 and 0.765, respectively. The optimal diagnostic threshold of HER2 overexpression group was 0.909; the sensitivity, specificity and accuracy were 0.547, 0.667 and 0.607, respectively. 【Conclusion】 Normalized ADC is negatively correlated with HER2 expression. ADC may be a potential marker for predicting HER2 expression.

Tra2β Enhances Cell Proliferation by Inducing the Expression of Transcription Factor SP1 in Cervical Cancer / 生物医学与环境科学（英文）

OBJECTIVE@#In this study, the role and potential mechanism of transformer 2β (Tra2β) in cervical cancer were explored.@*METHODS@#The transcriptional data of Tra2β in patients with cervical cancer from Gene Expression Profiling Interactive Analysis (GEPIA) and cBioPortal databases were investigated. The functions of Tra2β were evaluated by using Western blot, MTT, colony formation, Transwell assays, and nude mouse tumor formation experiments. Target genes regulated by Tra2β were studied by RNA-seq. Subsequently, representative genes were selected for RT-qPCR, confocal immunofluorescence, Western blot, and rescue experiments to verify their regulatory relationship.@*RESULTS@#The dysregulation of Tra2β in cervical cancer samples was observed. Tra2β overexpression in Siha and Hela cells enhanced cell viability and proliferation, whereas Tra2β knockdown showed the opposite effect. Alteration of Tra2β expression did not affect cell migration and invasion. Furthermore, tumor xenograft models verified that Tra2β promoted cervical cancer growth. Mechanically, Tra2β positively regulated the mRNA and protein level of SP1, which was critical for the proliferative capability of Tra2β.@*CONCLUSION@#This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo, which provides a comprehensive understanding of the pathogenesis of cervical cancer.

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma / 医学前沿

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

Perspective of Precision Therapy on Lung Cancer / 肿瘤防治研究

Lung cancer remains to have the highest morbidity and mortality rates in China among known malignant tumors. Novel drugs and regimens have been sought because of the limited efficiency of traditional chemotherapy and radiotherapy in lung cancer treatment. In the last 20 years, rapid developments in molecular targeted therapy and immunotherapy have increased clinical efficacy and benefitted patients with cancer. Treatments for lung cancer are the most rapidly developed among treatments for solid tumors, pioneering tumor precision medicine. This manuscript reviews the evolution and development of targeted therapy and immunotherapy and discusses existing problems and future directions in the precision therapy of lung cancer.

Progress of PARP inhibitors in targeted therapy of small cell lung cancer / 国际肿瘤学杂志

Small cell lung cancer (SCLC) is a rapidly developing malignant tumor, which is highly heterogeneous and prone to drug resistance, and the prognosis is usually poor. Poly ADP-ribose polymerase (PARP) inhibitors target the DNA damage response pathway, preventing DNA repair, thereby exerting anti-tumor effects. Currently, PARP inhibitors are used as monotherapy or in combination with DNA-damaging agents or immune checkpoint inhibitors in the treatment of SCLC. Although the current research results are limited, it can be seen that PARP inhibitors may be a breakthrough in the targeted therapy of SCLC.

Research progress on the application of combining radiotherapy and systemic therapy in breast cancer / 国际肿瘤学杂志

Compared with single therapy, radiotherapy combined with chemotherapy, endocrine therapy, molecular targeted therapy and immunological therapy can not only shorten the treatment cycle, but also improve the local control rate and prolong the survival of patients. However, the safety of combined therapy still needs to be further clarified to comprehensively evaluate the feasibility. Therefore, exploring the efficacy and safety of radiotherapy combined with systematic therapy will provide evidence for clinical benefits.

Research progress of solute carriers related genes in malignant tumors / 国际肿瘤学杂志

As a transport channel for amino acids, solute carrier (SLC) exists in all kinds of cells, and its function is to transport various amino acids and provide necessary nutrients for the growth and development of cells. In recent years, SLC7A5 and SLC7A11 genes of SLC7 family members have been found to be highly expressed in various malignant tumors, which can promote the occurrence and development of tumors by providing necessary amino acids for tumors. Studies have shown that these genes are associated with a variety of malignant tumors, and their expression is closely related to the growth, metastasis, treatment and prognosis of tumor cells. Moreover, the results of multiple studies suggest that SLC7A5 and SLC7A11 genes can be used as therapeutic targets for malignant tumors. Clarifying the expression and clinical significance of the above genes in malignant tumors, the molecular biological mechanism and the progress of molecular targeted therapy are helpful to provide a new way for the diagnosis and treatment of malignant tumors.

Research progress on targeted therapy of breast cancer with low expression of HER2 / 国际肿瘤学杂志

Breast cancer has become the malignant tumor with the highest incidence rate among women, of which human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for about 15%-20%. With the development of anti HER2 targeted drugs, the survival and prognosis of HER2 positive breast cancer has significantly benefited. About 45%-55% of breast cancer patients have low HER2 expression, and these patients usually do not receive anti HER2 treatment. However, there is a significant difference between the biological behavior and prognosis of breast cancer with low HER2 expression and breast cancer with zero HER2 expression. It is helpful to differentiate and adopt corresponding treatment strategies to improve the prognosis of patients. At present, there have been many advances in targeted therapy of breast cancer with low HER2 expression, which provides a useful reference for precision treatment of breast cancer with low HER2 expression.

Treatment status of non-small cell lung cancer with METexon14 skipping mutation / 国际肿瘤学杂志

MET exon14 (METex14) skipping mutation is an independent driver gene in non-small cell lung cancer (NSCLC) . About 3%-4% of NSCLC patients carry METex14 skipping mutation. These patients have poor prognoses and poor responses to traditional chemotherapy and immunotherapy. Highly selective MET inhibitors such as capmatinib, tepotinib, savolitinib have shown good efficacy and safety data in clinical trials, which bring new treatment options for patients with METex14 skipping mutations.

Progress of companion diagnostics in chimeric antigen receptor T-cell therapy / 白血病·淋巴瘤

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved good efficacy in treatment of hematological malignancies. As a precise and individualized treatment method, CAR-T is gradually moving towards commercialization. In addition to the introduction of corresponding policies and guiding principles, the related detection protocols should also be updated and improved to maximize its effect and achieve precise individualization. This article introduces and expands the concept of "companion diagnostics" that first appeared in targeted drugs, and introduces the significances of various detection technologies and biomarkers for patient screening, safety monitoring and evaluation of efficacy and CAR-T function in the whole process of CAR-T treatment.

Progress of minimal residual disease surveillance in B-cell lymphoma / 白血病·淋巴瘤

B-cell lymphoma is a group of heterogeneous hematologic malignant tumors originating from B cells, and it could be divided into invasive B-cell lymphoma and inert B-cell lymphoma. Currently, although disease remission rate has reached a high level, some patients still develop disease relapse or progression, thus, it is important to regularly monitor the disease and early identify the recurrence. At present, the recurrence of lymphoma mainly depends on imaging and clinical evaluation. However, some studies have shown that the minimal residual disease (MRD) monitoring based on flow or second-generation sequencing can provide a more accurate assessment of the depth of remission, predict the disease prognosis, and identify the early disease recurrence. This review summarizes the application of MRD in indolent lymphoma and aggressive lymphoma, mainly including the detection methods of MRD, research status and the application prospect of MRD in different lymphomas.

Progress of gene alterations and molecular typing of peripheral T-cell lymphoma / 白血病·淋巴瘤

Peripheral T-cell lymphoma (PTCL) is a group of heterogeneous malignant tumors with poor prognosis, with a lack of standard treatment regimen and poor efficacy of traditional chemotherapy. Therefore, finding new and more effective therapeutic targets to improve the efficacy of PTCL is an urgent clinical problem. In recent years, as the exploration of PTCL at the genetic and molecular levels has intensified, novel therapeutic targets based on gene alterations and molecular typing have been identified. This article summarizes the research progress of main gene alterations and molecular typing of PTCL in recent years.

Diagnosis and treatment progress of primary central nervous system lymphoma / 白血病·淋巴瘤

Primary central nervous system lymphoma (PCNSL) is a rare lymphoma type. The prognosis of PCNSL patients after treated by traditional therapy regimen is very poor. The way to evaluate the prognosis of PCNSL and to increase therapeutic efficacy have become the clinical problem. The 64th American Society of Hematology (ASH) annual meeting reported the latest research progress of diagnosis and treatment of PCNSL, including image examination, genetic sequencing, targeted therapy, chimeric antigen receptor T-cell (CAR-T) therapy and autologous hematopoietic stem cell transplantation (ASCT). This paper reviews the latest progress of PCNSL in the 64th ASH annual meeting.

Progress of small molecule targeted therapy for acute myeloid leukemia / 白血病·淋巴瘤

Acute myeloid leukemia (AML) is the most common subtype of acute leukemia in adults with significant heterogeneity. Among hematological malignancies, targeted therapy for AML comes relatively late. Although traditional chemotherapy is still an indispensable part of AML treatment, more and more small molecule targeted drugs have been used in recent years since 2017. This article reviews the progress of small molecule targeted drugs for AML at the 64th American Society of Hematology annual meeting.

Treatment progress of relapsed/refractory follicular lymphoma / 白血病·淋巴瘤

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. The outcome of relapsed/refractory FL patients after multi-therapy is poor. The 64th American Society of Hematology annual meeting in 2022 announced the latest updates on relapsed/refractory FL, including targeted therapy, bio-specific antibodies and chimeric antigen receptor T-cell. This review provides an overview of these updates.

Connexin 43: A new therapeutic target against blinding eye diseases / 国际眼科杂志(Guoji Yanke Zazhi)

The major blinding eye diseases, such as keratitis, cataract, glaucoma, diabetic retinopathy, seriously threaten human health and affect the quality of patients' life. Connexin 43(Cx43), as the most common connexin in vertebrates, is widely distributed in eye tissues and is involved in physiological processes such as embryonic development, metabolic regulation, tissue homeostasis, as well as pathological processes such as inflammation, oxidative stress, epithelial-mesenchymal transition, vascular leakage, and angiogenesis. Cx43 plays an important role in the occurrence and development of various blinding eye diseases. This article will review its role in the pathogenesis of the above-mentioned blinding eye diseases and the advances in targeting Cx43 therapy.