Tislelizumab for squamous lung cancer combined with basal cell carcinoma of the skin: A case report.

INTRODUCTION: Surgery is the preferred treatment for basal cell carcinoma (BCC), locally advanced or metastatic BCC, radiation therapy or systemic therapy can be considered. Programmed death receptor 1 (PD-1) inhibitors are rarely used to treat cutaneous BCC. In the present case, we found that tislelizumab, a PD-1 immunosuppressant, had a positive effect on BCC. PATIENT CONCERNS: A 74-year-old male patient presented with a mass in the left back in October 2021, which was surgically removed and diagnosed as BCC. The patient was diagnosed with squamous lung cancer after presenting with a cough and coughing up a small amount of white, sticky sputum in December 2021. DIAGNOSIS: BCC and squamous lung cancer. INTERVENTIONS: Docetaxel + nedaplatin systemic chemotherapy combined with tislelizumab immunotherapy. OUTCOMES: Both BCC and squamous lung cancer were significantly reduced in size. CONCLUSION: After 2 cycles of immunotherapy with tislelizumab, the lung tumor shrank, the back mass disappeared, and the wound healed.

Province-specific alcohol-attributable cancer deaths and years of potential life lost in China.

OBJECTIVE: Cancer is a major cause of death in China. As alcohol drinking, a risk factor of cancer, is common in China, we aimed to estimate the alcohol-attributable cancer deaths and years of potential life lost (YPLL) across all provinces in China. METHODS: We estimated the proportion of cancer deaths and YPLL attributable to alcohol consumption at the province level. Population attributable fraction (PAF) was calculated based on: 1) prevalence of alcohol consumption, obtained from the China National Nutrition and Health Survey 2002; 2) dose-response relative risks (RRs) of alcohol consumption and site-specific cancer, extracted from published meta-analyses; 3) cancer mortality data, originated from the National Program of Cancer Registry 2013. RESULTS: We estimated that 98,306 cancer deaths were attributable to alcohol consumption and accounted for 4.56 % of the total cancer deaths in China in 2013. Of these deaths, a total of 919,741.57 person-years premature loss of life was caused. Both overall PAF and average YPLL per 100,000 individuals were much higher in men than that in women (7.01 % vs. 0.33 % and 130.55 vs. 4.45, respectively). At the province level, overall PAF ranged from 2.14 % (95 % CI: 1.40 %-2.87 %) in Shanghai to 6.56 % (95 % CI: 4.06 %-9.05 %) in Anhui and the average YPLL per 100,000 individuals ranged from 10.97 in Tibet to 106.52 in Shandong. CONCLUSIONS: Cancer burden attributable to alcohol consumption varied across provinces in China. Province-level approaches are warranted to decrease alcohol consumption and reduce the alcohol-related cancer burden.

Amyloid ß Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease.

BACKGROUND: Amyloid ß (Aß) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aß accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. METHODS: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aß (oAß) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. RESULTS: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAß (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation. CONCLUSIONS: oAß-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.

A parallel study of careHPV and Hybrid Capture 2 human papillomavirus DNA testing for cervical cancer screening in rural China.

Hybrid Capture 2 (HC2) has been demonstrated to be a feasible screening method for cervical cancer. Based upon HC2 technology, careHPV is a simple, rapid, accurate, and inexpensive screening test for women in low-resource settings. This study aims to characterize both the careHPV test and HC2 test, and to compare careHPV results of specimens stored in careHPV test collection medium (TCM) to HC2 results from partner specimens stored in Qiagen specimen transport medium and TCM. The positive rates of high-risk HPV in careHPV, HC2, and HC2 (TCM) were 13.2% (108/818), 13.2% (108/818), and 13.6% (111/818), respectively. The agreement rates of pairwise tests were 95.8% (95% CI: 94.5-97.2%), 96.7% (95% CI: 95.5-97.9%), and 97.2% (95% CI: 96.1-98.3%), respectively. The Kappa values of the pairwise tests were 0.82 (95% CI: 0.76-0.88), 0.86 (95% CI: 0.81-0.91), and 0.88 (95% CI: 0.83-0.93), respectively. Based on these findings, although careHPV is demonstrated to be a viable alternative to the HC2 test, improvements on the careHPV test are still required prior to its implementation as a suitable screening method for women in low-resource settings. Further studies on the significance and applicability of the careHPV test must be performed.

Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats.

Accumulating data suggest that inflammation may contribute to epileptogenesis in experimental models as well as in humans. However, whether anti-inflammatory treatments can prevent epileptogenesis still remains controversial. Here, we examined the anti-epileptogenic effect and possible mechanisms of aspirin, a non-selective Cyclooxygenase (COX) inhibitor, in a rat model of lithium-pilocarpine-induced status epilepticus (SE). Epileptic rats were treated with aspirin (20mg/kg) at 0h, 3h, or 24h after the termination of SE, followed by once daily treatment for the subsequent 20 days. We found that aspirin treatment significantly reduced the frequency and duration of spontaneous recurrent seizures during the chronic epileptic phase. Hippocampal neuronal loss five weeks after SE was also attenuated in the CA1, CA3 and hilus following aspirin administration. Furthermore, the aberrant migration of newly generated granule cells and the formation of hilar basal dendrites were prevented by aspirin. Treatment with aspirin starting at 3h or 24h after SE also suppressed the development of mossy fiber sprouting. These findings suggest the possibility of a relative broad time-window for aspirin intervention in the epileptogenic process after injury. Aspirin may serve as a potential adjunctive therapy for individuals susceptible to chronic epilepsy.

LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats.

Depressed patients with increased inflammatory cytokines in peripheral blood have been reported to be more likely to exhibit treatment resistance. However, it is unknown whether the inflammation influences the action of antidepressant drugs. Here, we investigated the influence of lipopolysaccharide (LPS) on the antidepressant action of fluoxetine in depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, we first modified the CUMS paradigm by administration of LPS daily before the stressor, and then investigated the influence of inflammation on the antidepressant action of fluoxetine. The effects of stress exposure and antidepressant treatment were assessed by behavioral testing (sucrose preference test, forced swimming test, novelty suppressed feeding test) and hippocampal BrdU labeling. The CUMS-induced behavioral changes can be reversed by 4-week fluoxetine treatment. Fluoxetine also increased the hippocampal neurogenesis in the depressive rats. Pretreatment with LPS, to mimic inflammation, had no significant effect on depressive behavior but attenuated the antidepressant action of fluoxetine significantly. Thus, our results suggest that the inflammation might play a certain role in the pathophysiology of antidepressant treatment resistance.

[Efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope].

OBJECTIVE: To explore the efficacy of midodrine hydrochloride in the treatment of vasovagal syncope (VVS) in children. METHODS: Forty-eight children with unexplained syncope and prodromata (21 males, 27 females, aged 6 -17 years, mean 11 years +/- 3 years) were randomly assigned into 3 groups. They were health education group, cresol group and midodrine hydrochloride group respectively. Cresol group was comprised of children given cresol as first-line therapy in addition to health education and midodrine hydrochloride group patients given midodrine hydrochloride on the basis of cresol group. Repeated head-up tilt testing (HUTT) and follow-ups of at least 6 months were conducted to evaluate the therapeutic efficacy, side effects of midodrine hydrochloride and hemodynamic changes in treating pediatric VVS. RESULTS: (1) The HUTT-based effective rate of 3 group was 20.0% (2/10), 60.9% (14/23) and 80.0% (12/15) respectively. It was significantly higher in cases of midodrine hydrochloride group and cresol group than that of health education group (P < 0.05). However,there was no significant difference in the HUTT-based effective rate between cresol group and midodrine hydrochloride group (P > 0.05). (2) During the follow-up period, the recurrence rate of syncope was significantly lower in midodrine hydrochloride group than in other two groups (P < 0.05). However, there was no significant difference in the recurrence rate of syncope between health education and cresol groups (P > 0.05). (3) There was no statistic difference in supine hemodynamic indices (HR, SBP, DBP) between before and after treatment in 3 groups. After midodrine therapy, the effects of midodrine upon changes in systolic and diastolic pressures and heart rate, between upright beginning and supine positions, were statistically significant (P <0.05). CONCLUSION: Health education and cresol are conventional therapies for pediatric VVS. The efficacy can be enhanced by supplementing midodrine hydrochloride. Such a regimen is effective and safe in treating pediatric VVS.

A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage.

Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses. In response to IR, ATM phosphorylates I-2 on serine 43, leading to the dissociation of the PP1-I-2 complex and the activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in the inhibition of the Aurora-B kinase, the down-regulation of histone H3 serine 10 phosphorylation, and the activation of the G(2)/M checkpoint. Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage.

Clofarabine acts as radiosensitizer in vitro and in vivo by interfering with DNA damage response.

PURPOSE: Combination treatment with radiotherapy and chemotherapy has emerged as the dominant form of cancer adjuvant regimens in recent years. Clofarabine, a newly approved drug for pediatric leukemia, is a second-generation purine nucleoside analogue that can block DNA synthesis and inhibit DNA repair. Therefore, we hypothesized that clofarabine could work synergistically with radiotherapy to increase the tumor cell response. METHODS AND MATERIALS: The effects of clofarabine on radiosensitivity have been established in several tumor cell lines in vitro and in vivo using colony-forming assays and tumor xenografts. The effect of clofarabine on the DNA damage response was also studied in vitro by measuring gamma-H2AX focus formation. RESULTS: Clonogenic survival was significantly reduced in irradiated cells treated with clofarabine, demonstrating the strong radiosensitizing effect of clofarabine. Furthermore, clofarabine displayed a radiosensitizing effect that was greater than gemcitabine or 5-fluorouracil. We also found that low doses of clofarabine can prolong the presence of radiation-induced gamma-H2AX nuclear focus formation, and high doses of clofarabine can induce DNA double-strand breaks, suggesting that clofarabine can interfere with DNA damage response pathways. In addition, clofarabine-induced radiosensitization was also established in vivo using a colorectal cancer model, DLD-1, in athymic nude mice. When combined with fractionated radiotherapy, a moderate dose of clofarabine led to a significant increase in tumor growth inhibition. CONCLUSION: Clofarabine acts as a powerful radiosensitizer both in vitro and in vivo by interfering with the DNA damage response.

Characterization of an NBS1 C-terminal peptide that can inhibit ataxia telangiectasia mutated (ATM)-mediated DNA damage responses and enhance radiosensitivity.

ATM and NBS1, mutation of which lead to the human autosomal recessive diseases ataxia telangiectasia and Nijmegen breakage syndrome (NBS), respectively, are essential elements in the cellular response to DNA damage induced by ionizing radiation (IR). ATM is a member of the phosphatidylinositol 3-kinase family and is activated by IR in an NBS1-dependent manner. The extreme C terminus of NBS1 contains an evolutionarily conserved sequence motif that is critical for binding to and activation of ATM after IR. ATM phosphorylates a series of targets to initiate cell cycle arrest and promote cell survival in response to DNA damage. Therefore, targeting the NBS1-ATM interaction may lead to a novel approach for specific ATM inhibition and radiosensitization. We developed small peptides containing the conserved C-terminal sequence of NBS1 to investigate whether these peptides can interfere with the DNA damage pathway. We found that wild-type NBS1 inhibitory peptides (wtNIP) can abrogate NBS1-ATM association in the presence or absence of IR. We also found that cells exposed to wtNIP displayed a significant reduction in radiation-induced gamma-H2AX and NBS1 focus formation compared with cells treated with control peptides, demonstrating that wtNIP possesses a strong inhibitory effect on ATM. The inhibitory effect of wtNIP also leads to a significant decrease in clonogenic survival in response to IR. Furthermore, wtNIP does not radiosensitize cells with defective ATM, suggesting a specific inhibition of ATM. Together, these data provide a proof of principle for the use of NBS1 C-terminal small peptides as specific ATM inhibitors and radiosensitizers.

[The efficacy and mechanism of rhIL-11 in the management of chemotherapy-induced thrombocytopenia in acute leukemia].

OBJECTIVE: To investigate the efficacy, safety and possible mechanism of rhIL-11 in the management of chemotherapy-induced thrombocytopenia in acute leukemia. METHODS: Thirty-two acute leukemia patients were enrolled in the study. rhIL-11 was given when platelet count dropped below 30 x 10(9)/L after chemotherapy, at 1.5 mg/d, ih, for 7-14 days or withdrawn when the increase of platelet count was more than 50 x 10(9)/L. Serum IL-11 level was determined by ELISA, IL-11R alpha gene expression by RT-PCR. Efficacy and safety data were collected and their correlation with serum IL-11 and IL-11Ralpha expression were analyzed. RESULTS: The platelet counts on day 7 and 14 after medication were (63.40 +/- 7.24) x 10(9)/L and (98.70 +/- 9.37) x 10(9)/L for 32 patients in IL-11 group [26 complete remission (CR), 2 partial remission (PR), 4 non-remission (NR)] and (42.50 +/- 6.38) x 10(9)/L and (70.30 +/- 7.12) x 10(9)/L for the control group (20 CR, 3 PR, 5 NR). There were 10 patients who received platelet transfusion (16-32 U) in IL-11 group and 19 patients (32-48 U) in control group. Compared with the IL-11 group a delay of platelet recovery was observed in controls (P < 0.05). IL-11 was generally well tolerated. Five experienced transient atrial arrhythmia and relieved after extenuation or withdrawal. The responders' serum IL-11 level of pre-medication was (21.81 +/- 1.88) ng/L, lower than that of non-responders (P < 0.05). IL-11Ralpha level was 0.3552 +/- 0.0224, higher than that of non-responders (P < 0.05). No correlation was observed among serum IL-11, IL-11Ralpha expression, platelet count, and megakaryocyte number. CONCLUSIONS: rhIL-11 can safely accelerate the recovery of chemotherapy-induced thrombocytopenia in acute leukemia. The serum IL-11 level and IL-11Ralpha of mononuclear cells might predict the efficacy of rhIL-11.