RESUMO
Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.
Assuntos
Imunoconjugados , Leucemia de Células T , Linfoma de Células T , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Animais , Feminino , Humanos , Camundongos , Imunoconjugados/imunologia , Imunoconjugados/uso terapêutico , Imunoterapia Adotiva , Leucemia de Células T/tratamento farmacológico , Leucemia de Células T/imunologia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, NaV1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For NaV1.5, this process is critical as alterations in Na+ current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the autoregulatory mechanism of NEDD4L. Through in vitro and electrophysiological experiments, the NEDD4L 1,2-linker was determined to be important in substrate ubiquitination of NaV1.5. We establish the preferred sites of ubiquitination of NEDD4L to be in the second WW-linker (2,3-linker). Interestingly, NEDD4L ubiquitinates the cytoplasmic linker between the first and second transmembrane domains of the channel (DI-DII) of NaV1.5. Moreover, we design a genetically encoded modulator of Nav1.5 that achieves Na+ current reduction using the NEDD4L HECT domain as cargo of a NaV1.5-binding nanobody. These investigations elucidate the mechanisms regulating the NEDD4 family and furnish a new molecular framework for understanding NaV1.5 ubiquitination.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Canal de Sódio Disparado por Voltagem NAV1.5 , Ubiquitina-Proteína Ligases Nedd4 , Ubiquitinação , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina/metabolismo , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Células HEK293RESUMO
Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by "inverting" the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Perda de Heterozigosidade , Terapia de Alvo Molecular , Neoplasias/etiologia , Neoplasias/terapia , Alelos , Antígenos de Neoplasias/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Anticorpos de Cadeia Única/farmacologia , Anticorpos de Cadeia Única/uso terapêuticoRESUMO
The adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 degradation is a poorly understood biological phenomenon suggested to reduce TCR activation of NF-κB. Here we have shown that TCR engagement triggers the degradation of Bcl10 in primary effector T cells but not in naive T cells. TCR engagement promoted K63 polyubiquitination of Bcl10, causing Bcl10 association with the autophagy adaptor p62. Paradoxically, p62 binding was required for both Bcl10 signaling to NF-κB and gradual degradation of Bcl10 by autophagy. Bcl10 autophagy was highly selective, as shown by the fact that it spared Malt1, a direct Bcl10 binding partner. Blockade of Bcl10 autophagy enhanced TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a pathway-intrinsic homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. This homeostatic process may protect T cells from adverse consequences of unrestrained NF-κB activation, such as cellular senescence.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Autofagia/fisiologia , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Relacionadas à Autofagia , Proteína 10 de Linfoma CCL de Células B , Caspases/fisiologia , Diferenciação Celular , Citosol/imunologia , Citosol/ultraestrutura , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/fisiologia , Homeostase , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/fisiologia , Fagossomos/fisiologia , Fagossomos/ultraestrutura , Mapeamento de Interação de Proteínas , Proteína Sequestossoma-1 , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/ultraestrutura , Células Th2/imunologia , Células Th2/ultraestrutura , Enzimas de Conjugação de Ubiquitina/fisiologiaRESUMO
: Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. â¯: We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. â¯: We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P = .17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P = .05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD. â¯: ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.
Assuntos
Doença Enxerto-Hospedeiro , Doença de Hodgkin , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença de Hodgkin/terapia , Humanos , Inibidores de Checkpoint Imunológico , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Allogeneic blood or marrow transplantation (allo-BMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. Although post-transplantation cyclophosphamide (PTCy) reduces allo-BMT toxicity by decreasing the risk of graft-versus-host disease (GVHD), its effect on CLL allo-BMT outcomes is unknown. We studied 64 consecutive patients with CLL who underwent nonmyeloablative (NMA) haploidentical allo-BMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this cohort, the 4-year overall survival was 52% (95% confidence interval [CI], 40% to 68%), and progression-free survival was 37% (95% CI, 26% to 54%). Six patients experienced engraftment failure. PTCy prophylaxis was associated with a modest cumulative incidence of 1-year grade II-IV acute GVHD (27%; %95% CI, 15% to 38%) and %%%2-year chronic GVHD (17%; 95% CI, 7% to 26%). We demonstrate that NMA haploidentical allo-BMT with PTCy is a safe and effective treatment option.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Medula Óssea , Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Linfocítica Crônica de Células B/terapiaRESUMO
Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6·1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0·005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia Adotiva , Linfoma não Hodgkin , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.
Assuntos
Doença de Hodgkin , Inibidores de Checkpoint Imunológico , Estudos de Coortes , Doença de Hodgkin/tratamento farmacológico , Humanos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS: Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS: Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION: In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE: Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.
Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica , Canadá , Doença de Hodgkin/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia , Estudos Prospectivos , Qualidade de Vida , Estudos RetrospectivosRESUMO
After T cell receptor (TCR) engagement, the CARD11-Bcl10-Malt1 (CBM) complex oligomerizes to transduce NF-κB activating signals. Bcl10 is then degraded to limit NF-κB activation. The cDNA AK057716 (BinCARD-1) was reported to encode a novel CARD protein that interacts with Bcl10 and modestly inhibits NF-κB activation. In a later study, a second isoform, BinCARD-2, was identified. Here, we report that the cDNA AK057716 (BinCARD-1) is an incompletely spliced derivative of the gene product of C9orf89, whereas CARD19 (BinCARD-2) represents the properly spliced isoform, with conservation across diverse species. Immunoblotting revealed expression of CARD19 in T cells, but no evidence of BinCARD-1 expression, and microscopy demonstrated that endogenous CARD19 localizes to mitochondria. Although we confirmed that both BinCARD-1 and CARD19 can inhibit NF-κB activation and promote Bcl10 degradation when transiently overexpressed in HEK293T cells, loss of endogenous CARD19 expression had little effect on Bcl10-dependent NF-κB activation, activation of Malt1 protease function, or Bcl10 degradation after TCR engagement in primary murine CD8 T cells. Together, these data indicate that the only detectable translated product of C9orf89 is the mitochondrial protein CARD19, which does not play a discernible role in TCR-dependent, Bcl10-mediated signal transduction to Malt1 or NF-κB.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Células Jurkat , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/genéticaRESUMO
Non-photochemical quenching (NPQ) in photosynthetic organisms provides the necessary photoprotection that allows them to cope with largely and quickly varying light intensities. It involves deactivation of excited states mainly at the level of the antenna complexes of photosystem II using still largely unknown molecular mechanisms. In higher plants the main contribution to NPQ is the so-called qE-quenching, which can be switched on and off in a few seconds. This quenching mechanism is affected by the low pH-induced activation of the small membrane protein PsbS which interacts with the major light-harvesting complex of photosystem II (LHCII). We are reporting here on a mechanistic study of the PsbS-induced LHCII quenching using ultrafast time-resolved chlorophyll (Chl) fluorescence. It is shown that the PsbS/LHCII interaction in reconstituted proteoliposomes induces highly effective and specific quenching of the LHCII excitation by a factor ≥ 20 via Chl-Chl charge-transfer (CT) state intermediates which are weakly fluorescent. Their characteristics are very broad fluorescence bands pronouncedly red-shifted from the typical unquenched LHCII fluorescence maximum. The observation of PsbS-induced Chl-Chl CT-state emission from LHCII in the reconstituted proteoliposomes is highly reminiscent of the in vivo quenching situation and also of LHCII quenching in vitro in aggregated LHCII, indicating a similar quenching mechanism in all those situations. The PsbS mutant lacking the two proton sensing Glu residues induced significant, but much smaller, quenching than wild type. Added zeaxanthin had only minor effects on the yield of quenching in the proteoliposomes. Overall our study shows that PsbS co-reconstituted with LHCII in liposomes represents an excellent in vitro model system with characteristics that are reflecting closely the in vivo qE-quenching situation.
Assuntos
Proteínas de Arabidopsis/química , Arabidopsis/química , Complexos de Proteínas Captadores de Luz/química , Complexo de Proteína do Fotossistema II/química , Proteolipídeos/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Clorofila/química , Clorofila/metabolismo , Fluorescência , Concentração de Íons de Hidrogênio , Complexos de Proteínas Captadores de Luz/genética , Complexos de Proteínas Captadores de Luz/metabolismo , Mutação , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Espectrometria de Fluorescência , Tilacoides/química , Zeaxantinas/químicaAssuntos
Artéria Pulmonar , Sarcoma , Neoplasias Vasculares , Humanos , Sarcoma/patologia , Sarcoma/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/patologia , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/patologia , Masculino , Túnica Íntima/patologia , Túnica Íntima/diagnóstico por imagem , Pessoa de Meia-Idade , Broncoscopia/métodos , Feminino , Criocirurgia/métodosAssuntos
Antígenos CD19 , Lúpus Eritematoso Sistêmico , Contagem de Células , Humanos , Linfócitos TRESUMO
OBJECTIVE: Limited information is available based on single-center studies on trends of incidence and outcomes in gastrointestinal (GI) bleed with shock. METHODS: We analyzed data from 2002 to 2013 National Inpatient Sample. Using ICD-9 codes we identified 6.4 million hospital discharges of GI bleed from National Inpatient Sample database. Events were analyzed based on type of GI bleed, in-hospital mortality, hemodynamic status, and use of blood products. RESULTS: GI bleed with shock results in higher hospital mortality (20.77% with shock vs. 2.6% without shock). Between 2002 and 2013, there has been an increase in the percentage of upper and lower GI bleed with shock (1.35% to 4.92% and 1.49% to 3.06%) along with a reduction in mortality in both upper GI bleed with shock (26.9% to 13.8%) and lower GI bleed with shock (54.7% to 19.7%). Consistent with the rise in GI bleed with shock was an increase in blood product utilization. Packed red blood cell (pRBC) transfusion was associated with reduction in mortality in both nonvariceal upper GI bleed with shock (18.3% without pRBC vs. 13.9% receiving pRBC) and lower GI bleed with shock (36.05% without pRBC vs. 22.13% receiving pRBC), but did not affect mortality in variceal upper GI bleed with shock (31.79% vs. 32.22%). CONCLUSIONS: GI bleed with shock carries a higher mortality and have been steadily increasing from 2002 to 2013. pRBC transfusion was associated in improved mortality in GI bleed with shock except variceal bleed.
Assuntos
Hemorragia Gastrointestinal/epidemiologia , Choque Séptico , Idoso , Feminino , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/mortalidade , Mortalidade Hospitalar/tendências , Humanos , Masculino , Estados Unidos/epidemiologiaRESUMO
Antigen stimulation of T cell receptor (TCR) signaling to nuclear factor (NF)-κB is required for T cell proliferation and differentiation of effector cells. The TCR-to-NF-κB pathway is generally viewed as a linear sequence of events in which TCR engagement triggers a cytoplasmic cascade of protein-protein interactions and post-translational modifications, ultimately culminating in the nuclear translocation of NF-κB. However, recent findings suggest a more complex picture in which distinct signalosomes, previously unrecognized proteins, and newly identified regulatory mechanisms play key roles in signal transmission. In this review, we evaluate recent data and suggest areas of future emphasis in the study of this important pathway.
Assuntos
Núcleo Celular/metabolismo , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Transporte Ativo do Núcleo Celular , Animais , Humanos , Ativação Linfocitária , Complexos Multiproteicos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologiaAssuntos
Hemangioma Capilar , Hipertensão Pulmonar , Neoplasias Pulmonares , Insuficiência Respiratória , Hemangioma Capilar/complicações , Hemangioma Capilar/diagnóstico , Humanos , Pulmão , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Insuficiência Respiratória/etiologiaRESUMO
BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disorder of unknown aetiology. Pulmonary involvement contributes substantially to its morbidity and mortality. Treatment of pulmonary disease due to SSc remains unsatisfactory. We examined the effect of sequential six-month intravenous pulse therapy with cyclophosphamide (CYC) followed by azathioprine and low-dose corticosteroids on SSc associated interstitial lung disease (SSc-ILD). METHODS: In a single-centre, prospective, observational, open-labelled study; nine patients (eight females, one male) with SSc-ILD were treated with intravenous pulse CYC (600mg/m(2) body surface area) at monthly interval for six cycles with oral prednisolone 10mg daily. Subsequently, azathioprine (2-3mg/Kg) was administered while continuing with the same dose of prednisolone. Primary end-points were forced vital capacity (FVC) and high resolution computed tomography (HRCT) scan of thorax score. Secondary end-points were quality of life measured by health assessment questionnaire-disability index (HAQ-DI) and six-minute walk distance (6WMD) test. RESULTS: After one year of observation, the FVC showed significant improvement (p=0.003). The 6WMD also improved significantly (p=0.0028). However, change in HRCT scan scoring and HAQ-DI score was not significant. CONCLUSIONS: Intravenous, pulse CYC followed by azathioprine along with low-dose corticosteroids produces significant improvement in FVC and 6WMD at 12-month follow-up without significant change in radiological manifestations and health status.
Assuntos
Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Escleroderma Sistêmico/complicações , Adulto , Azatioprina/administração & dosagem , Ciclofosfamida/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Masculino , Prednisolona/uso terapêutico , Estudos Prospectivos , Radiografia Torácica , Capacidade Vital , Teste de CaminhadaRESUMO
Familial spontaneous pneumothorax is one of the phenotypes of Birt-Hogg-Dubé syndrome (BHDS), an autosomal dominant condition associated with folliculin (FLCN). We investigated clinical and genetic data of an Indian family having two patients suffering from spontaneous pneumothorax in the absence of skin lesions or renal tumors. HRCT scan of patient's lung revealed paracardiac cysts, and DNA sequencing of all 14 exons of FLCN from patients showed the presence of heterozygous "C allele" deletion in the poly-cytosine (poly-C) tract of exon 11 leading to truncated folliculin. This mutation was also observed in four asymptomatic members of the family. Our results confirmed the presence of deletion mutation in poly-C tract of FLCN in members of BHDS family. This is the first report of genetic insight in a BHDS family from India but in-depth studies with a larger sample set are necessary to understand mechanism of familial pneumothorax.
Assuntos
Síndrome de Birt-Hogg-Dubé/genética , Análise Mutacional de DNA , Pneumotórax/genética , Proteínas Proto-Oncogênicas/genética , Deleção de Sequência , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/fisiopatologia , Éxons , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Índia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Pneumotórax/diagnóstico , Pneumotórax/fisiopatologia , Testes de Função Respiratória , Tomografia Computadorizada por Raios XRESUMO
Currently, sea turtle habitats are being altered by climate change and human activities, with habitat loss posing an urgent threat to Indian sea turtles. Thus, the objective of this study is to analyze the dynamic shoreline alterations and their impacts on Olive Ridley Sea Turtle (ORT) nesting sites in Gahirmatha Marine Wildlife Sanctuary from 1990 to 2022. Landsat satellite images served as input datasets to assess dynamic shoreline changes. This study assessed shoreline alterations and their rates across 929 transects divided into four zones using the Digital Shoreline Analysis System (DSAS) software. The results revealed a significant 14-km northward shift in the nesting site due to substantial coastal erosion, threatening the turtles' Arribada. This study underscores the need for conservation efforts to preserve nesting environments amidst changing coastal landscapes, offering novel insights into the interaction between coastal processes and marine turtle nesting behaviors.
Assuntos
Conservação dos Recursos Naturais , Ecossistema , Comportamento de Nidação , Tartarugas , Animais , Tartarugas/fisiologia , Índia , Monitoramento Ambiental , Mudança ClimáticaRESUMO
Microplastics are pervasive in the natural environment and pose a growing concern for global health. Plastic waste in marine environments has emerged as a global issue, threatening not only marine biota but also human health due to its implications for the food chain. This study aims to discern the patterns and trends of research, specifically on Marine Microplastic Pollution (MMP), based on a bibliometric analysis of scientific publications from 2011 to 2022. The methodology utilized in this study comprises three stages: (a) creating a bibliographical dataset from Scopus by Elsevier and the Web of Science Core Collection by Clarivate Analytics, (b) analyzing current research (trends and patterns) using bibliometric analysis through Biblioshiny tool, and (c) examining themes and subthemes in MMP research (wastewater treatment, plastic ingestion, the Mediterranean Sea, microplastics pollution, microplastics in freshwater, microplastic ingestion, plastic pollution, and microplastic pollution in the marine environment). The findings reveal that during the studied period, the number of MMP publications amounted to 1377 articles, with an average citation per publication of 59.23 and a total citation count of 81,553. The most cited article was published in 2011, and since then, the number of publications on this topic has been increasing steadily. The author count stood at 5478, with 22 trending topics identified from the 1377 published titles. Between 2019 and 2022, the countries contributing most to the publication of MMP articles were China, the United States of America (USA), and the United Kingdom (UK). However, a noticeable shift in the origin of author countries was observed in the 2019-2022 timeframe, transitioning from a dominance by the USA and the UK to a predominance by China. In 2019, there was a substantial increase in the volume of publications addressing the topic of microplastics. The results show that the most prevalent themes and subthemes pertained to MMP in the Mediterranean Sea. The journals with the highest number of MMP articles published were the Marine Pollution Bulletin (253 articles) and Science of the Total Environment (190 articles). The analysis concludes that research on MMP remains prominent and appears to be increasing each year.